116 results on '"Levin MC"'
Search Results
2. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
- Author
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Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, Frank JA, Galetta SL, Grossman RI, Hawker K, Kachuck NJ, Levin MC, Phillips JT, Racke MK, Rivera VM, Stuart WH, American Academy of Neurology. Therapeutics and Technology Assessment Subcommittee, Frohman, E M, Goodin, D S, and Calabresi, P A
- Published
- 2003
- Full Text
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3. Clinical stabilization of a multiple sclerosis patient after tonsillectomy.
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Levin MC and Wren T
- Published
- 2005
4. 'Not multiple sclerosis' and the changing face of HTLV-1: a case report of downbeat nystagmus.
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Daroff RB, Dell'osso LF, Frohman Faan EM, Beeravolu LR, Frohman Ba TC, Remington Rn Bsn Mscn GM, Lee S, and Levin MC
- Published
- 2009
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5. Pearls & Oy-sters: 'Not multiple sclerosis' and the changing face of HTLV-1: A case report of downbeat nystagmus.
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Beeravolu LR, Frohman EM, Frohman TC, Remington GM, Lee S, and Levin MC
- Published
- 2009
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6. The utility of MRI in suspected MS - Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology
- Author
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Michael C. Levin, Norman J Kachuck, Michael K. Racke, Steven Galetta, Robert I. Grossman, W. H. Stuart, John R. Corboy, Douglas S. Goodin, Elliot M. Frohman, Massimo Filippi, Patricia K. Coyle, Peter A. Calabresi, Kathleen Hawker, JT Phillips, Joseph A. Frank, Victor M. Rivera, Frohman, Em, Goodin, D, Calabresi, Pa, Corboy, Jr, Coyle, Pk, Filippi, Massimo, Frank, Ja, Galetta, Sl, Grossman, Ri, Hawker, K, Kachuck, Nj, Levin, Mc, Phillips, Jt, Racke, Mk, Rivera, Vm, and Stuart, Wh
- Subjects
Adult ,medicine.medical_specialty ,Clinically isolated syndrome ,Neurology ,Multiple Sclerosis ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Research ,Magnetic resonance imaging ,Gadolinium ,Middle Aged ,medicine.disease ,Prognosis ,Magnetic Resonance Imaging ,Sensitivity and Specificity ,Hyperintensity ,Central nervous system disease ,medicine ,Humans ,Neurology (clinical) ,Medical diagnosis ,business ,Nuclear medicine ,Prospective cohort study - Abstract
Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.
- Published
- 2003
7. RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.
- Author
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Messmer ML, Salapa HE, Popescu BF, and Levin MC
- Abstract
Objective: Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS., Methods: Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration., Results: We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1
high ) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low ), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases., Interpretation: hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024., (© 2024 American Neurological Association.)- Published
- 2024
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8. Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis.
- Author
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Frank C, Salapa HE, Allen KJH, Levin MC, Dawicki W, and Dadachova E
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- Animals, Mice, Antibodies, Monoclonal, T-Lymphocytes immunology, Female, Disease Models, Animal, Multiple Sclerosis immunology, Multiple Sclerosis diagnostic imaging, Positron Emission Tomography Computed Tomography methods, Humans, Encephalomyelitis, Autoimmune, Experimental immunology, Programmed Cell Death 1 Receptor immunology, Lymphocyte Activation immunology, Mice, Inbred C57BL
- Abstract
Long-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice. We also investigated the upregulation of PD-1 on infiltrating lymphocytes in an animal model of MS. Finally, we demonstrate the (to our knowledge) first reported positron-emission tomography/computed tomography imaging of activated PD-1+ cells in the EAE animal model of MS. We found that the 177Lu radioisotope-labeled anti-PD-1 mAb demonstrated significant in vitro cytotoxicity toward activated CD4+PD-1+ T lymphocytes and led to significant reduction in overall disease progression in the EAE animal model. Our results show high expression of PD-1 on infiltrating lymphocytes in the spinal cords of EAE diseased animals. Positron-emission tomography/computed tomography imaging of the anti-PD-1 mAb demonstrated significant uptake in the cervical draining lymph nodes highlighting accumulation of activated lymphocytes. Targeted depletion of T lymphocytes using T cell activation markers such as PD-1 may present a novel method to reduce autoimmune attack and inflammation in autoimmune diseases such as MS. Development of multimodal nuclear theranostic agents may present the opportunity to monitor T cell activation via imaging radioisotopes and simultaneously treat MS using therapeutic radioisotopes., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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9. Regulation of stress granule formation in human oligodendrocytes.
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Pernin F, Cui QL, Mohammadnia A, Fernandes MGF, Hall JA, Srour M, Dudley RWR, Zandee SEJ, Klement W, Prat A, Salapa HE, Levin MC, Moore GRW, Kennedy TE, Vande Velde C, and Antel JP
- Subjects
- Humans, Stress Granules, Oligodendroglia, Cytokines metabolism, Stress, Physiological, Cytoplasmic Granules metabolism, Multiple Sclerosis metabolism
- Abstract
Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions., (© 2024. The Author(s).)
- Published
- 2024
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10. Role of Perilipins in Oxidative Stress-Implications for Cardiovascular Disease.
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Cinato M, Andersson L, Miljanovic A, Laudette M, Kunduzova O, Borén J, and Levin MC
- Abstract
Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia-reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs) are conserved intracellular organelles that enable the safe and stable storage of neutral lipids within the cytosol. LDs are coated with proteins, perilipins (Plins) being one of the most abundant. In this review, we will discuss the interplay between oxidative stress and Plins. Indeed, LDs and Plins are increasingly being recognized for playing a critical role beyond energy metabolism and lipid handling. Numerous reports suggest that an essential purpose of LD biogenesis is to alleviate cellular stress, such as oxidative stress. Given the yet unmet suitability of ROS as targets for the intervention of cardiovascular disease, the endogenous antioxidant capacity of Plins may be beneficial.
- Published
- 2024
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11. hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS).
- Author
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Salapa HE, Thibault PA, Libner CD, Ding Y, Clarke JWE, Denomy C, Hutchinson C, Abidullah HM, Austin Hammond S, Pastushok L, Vizeacoumar FS, and Levin MC
- Subjects
- Humans, Alternative Splicing, RNA, RNA Splicing genetics, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Multiple Sclerosis genetics
- Abstract
Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS., (© 2024. The Author(s).)
- Published
- 2024
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12. Task-oriented exercise effects on walking and corticospinal excitability in multiple sclerosis: protocol for a randomized controlled trial.
- Author
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Moslemi Z, Toledo-Aldana EA, Baldwin B, Donkers SJ, Eng JJ, Mondal P, de Zepetnek JOT, Buttigieg J, Levin MC, and Mang CS
- Abstract
Background: Multiple sclerosis (MS) is a degenerative disease of the central nervous system (CNS) that disrupts walking function and results in other debilitating symptoms. This study compares the effects of 'task-oriented exercise' against 'generalized resistance and aerobic exercise' and a 'stretching control' on walking and CNS function in people with MS (PwMS). We hypothesize that task-oriented exercise will enhance walking speed and related neural changes to a greater extent than other exercise approaches., Methods: This study is a single-blinded, three-arm randomized controlled trial conducted in Saskatchewan, Canada. Eligible participants are those older than 18 years of age with a diagnosis of MS and an expanded Patient-Determined Disease Steps (PDDS) score between 3 ('gait disability') and 6 ('bilateral support'). Exercise interventions are delivered for 12 weeks (3 × 60-min per week) in-person under the supervision of a qualified exercise professional. Interventions differ in exercise approach, such that task-oriented exercise involves weight-bearing, walking-specific activities, while generalized resistance and aerobic exercise uses seated machine-based resistance training of major upper and lower body muscle groups and recumbent cycling, and the stretching control exercise involves seated flexibility and relaxation activities. Participants are allocated to interventions using blocked randomization that stratifies by PDDS (mild: 3-4; moderate: 5-6). Assessments are conducted at baseline, post-intervention, and at a six-week retention time point. The primary and secondary outcome measures are the Timed 25-Foot Walk Test and corticospinal excitability for the tibialis anterior muscles determined using transcranial magnetic stimulation (TMS), respectively. Tertiary outcomes include assessments of balance, additional TMS measures, blood biomarkers of neural health and inflammation, and measures of cardiorespiratory and musculoskeletal fitness., Discussion: A paradigm shift in MS healthcare towards the use of "exercise as medicine" was recently proposed to improve outcomes and alleviate the economic burden of MS. Findings will support this shift by informing the development of specialized exercise programming that targets walking and changes in corticospinal excitability in PwMS., Trial Registration: ClinicalTrials.gov, NCT05496881, Registered August 11, 2022. https://classic., Clinicaltrials: gov/ct2/show/NCT05496881 . Protocol amendment number: 01; Issue date: August 1, 2023; Primary reason for amendment: Expand eligibility to include people with all forms of MS rather than progressive forms of MS only., (© 2023. The Author(s).)
- Published
- 2023
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13. Cardiomyocytes, sphingolipids and cardio myotoxicity.
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Levin MC, Andersson L, and Borén J
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- Humans, Myotoxicity, Ceramides, Membrane Lipids, Myocytes, Cardiac, Sphingolipids
- Abstract
Purpose of Review: Sphingolipids are structurally diverse membrane lipids localized in lipid bilayers. Sphingolipids are not only important structural components of cellular membranes, but they are also important regulators of cellular trafficking and signal transduction and are implicated in several diseases. Here, we review the latest insights into sphingolipids and their role in cardiac function and cardiometabolic disease., Recent Findings: The underlying mechanisms linking sphingolipids to cardiac dysfunction are still not fully clarified. Sphingolipids, and in particular ceramides, have emerged as important players in lipotoxicity, mediating inflammation, impaired insulin signalling and apoptosis. In addition, recent findings highlight the importance of glycosphingolipid homeostasis in cardiomyocyte membranes, where they are required to maintain β-adrenergic signalling and contractile capacity to preserve normal heart function. Thus, glycosphingolipid homeostasis in cardiac membranes characterizes a novel mechanism linking sphingolipids to cardiac disease., Summary: Modulation of cardiac sphingolipids may represent a promising therapeutic approach. Sustained investigation of the link between sphingolipids and cardiomyocyte function is therefore needed and we hope that this review may inspire researchers to further elucidate the action of these lipids., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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14. Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS.
- Author
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Tokarska N, Naniong JMA, Johnston JM, Salapa HE, Muir GD, Levin MC, Popescu BF, and Verge VMK
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- Animals, Mice, Mice, Inbred C57BL, Anaerobiosis, Oxygen, Female, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental therapy, Multiple Sclerosis pathology, Multiple Sclerosis therapy, Remyelination
- Abstract
Remyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non-invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed. EAE was induced by MOG
35-55 immunization in C57BL/6 female mice. EAE mice received either AIH (10 cycles-5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (control; 21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease score of 2.5. Mice were followed post-treatment for an additional 7d before assessing histopathology or 14d to examine maintenance of AIH effects. Alterations in histopathological correlates of multiple repair indices were analyzed quantitatively in focally demyelinated ventral lumbar spinal cord areas to assess AIH impacts. AIH begun at near peak disease significantly improved daily clinical scores/functional recovery and associated histopathology relative to Normoxia controls and the former were maintained for at least 14d post-treatment. AIH enhanced correlates of myelination, axon protection and oligodendrocyte precursor cell recruitment to demyelinated areas. AIH also effected a dramatic reduction in inflammation, while polarizing remaining macrophages/microglia toward a pro-repair state. Collectively, this supports a role for AIH as a novel non-invasive therapy to enhance CNS repair and alter disease course following demyelination and holds promise as a neuroregenerative MS strategy., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)- Published
- 2023
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15. Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.
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Laudette M, Lindbom M, Arif M, Cinato M, Ruiz M, Doran S, Miljanovic A, Rutberg M, Andersson L, Klevstig M, Henricsson M, Bergh PO, Bollano E, Aung N, Gustav Smith J, Pilon M, Hyötyläinen T, Orešič M, Perkins R, Mardinoglu A, Levin MC, and Borén J
- Subjects
- Animals, Mice, Energy Metabolism, Lipids, Mitochondria metabolism, Receptors, LDL genetics, Receptors, LDL metabolism, Subtilisin metabolism, Myocytes, Cardiac metabolism, Proprotein Convertase 9 genetics, Proprotein Convertase 9 metabolism
- Abstract
Aims: Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells., Methods and Results: Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism., Conclusion: PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2023
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16. Sequence- and structure-specific RNA oligonucleotide binding attenuates heterogeneous nuclear ribonucleoprotein A1 dysfunction.
- Author
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Clarke JP, Thibault PA, Fatima S, Salapa HE, Kalyaanamoorthy S, Ganesan A, and Levin MC
- Abstract
The RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (A1) regulates RNA metabolism, which is crucial to maintaining cellular homeostasis. A1 dysfunction mechanistically contributes to reduced cell viability and loss, but molecular mechanisms of how A1 dysfunction affects cell viability and loss, and methodologies to attenuate its dysfunction, are lacking. Utilizing in silico molecular modeling and an in vitro optogenetic system, this study examined the consequences of RNA oligonucleotide (RNAO) treatment on attenuating A1 dysfunction and its downstream cellular effects. In silico and thermal shift experiments revealed that binding of RNAOs to the RNA Recognition Motif 1 of A1 is stabilized by sequence- and structure-specific RNAO-A1 interactions. Using optogenetics to model A1 cellular dysfunction, we show that sequence- and structure-specific RNAOs significantly attenuated abnormal cytoplasmic A1 self-association kinetics and A1 cytoplasmic clustering. Downstream of A1 dysfunction, we demonstrate that A1 clustering affects the formation of stress granules, activates cell stress, and inhibits protein translation. With RNAO treatment, we show that stress granule formation is attenuated, cell stress is inhibited, and protein translation is restored. This study provides evidence that sequence- and structure-specific RNAO treatment attenuates A1 dysfunction and its downstream effects, thus allowing for the development of A1-specific therapies that attenuate A1 dysfunction and restore cellular homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Clarke, Thibault, Fatima, Salapa, Kalyaanamoorthy, Ganesan and Levin.)
- Published
- 2023
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17. hnRNP A1 dysfunction in oligodendrocytes contributes to the pathogenesis of multiple sclerosis.
- Author
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Jahanbazi Jahan-Abad A, Salapa HE, Libner CD, Thibault PA, and Levin MC
- Subjects
- Animals, Mice, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, RNA-Binding Proteins metabolism, RNA, Small Interfering, Multiple Sclerosis pathology, Encephalomyelitis, Autoimmune, Experimental
- Abstract
Oligodendrocyte (OL) damage and death are prominent features of multiple sclerosis (MS) pathology, yet mechanisms contributing to OL loss are incompletely understood. Dysfunctional RNA binding proteins (RBPs), hallmarked by nucleocytoplasmic mislocalization and altered expression, have been shown to result in cell loss in neurologic diseases, including in MS. Since we previously observed that the RBP heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was dysfunctional in neurons in MS, we hypothesized that it might also contribute to OL pathology in MS and relevant models. We discovered that hnRNP A1 dysfunction is characteristic of OLs in MS brains. These findings were recapitulated in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, where hnRNP A1 dysfunction was characteristic of OLs, including oligodendrocyte precursor cells and mature OLs in which hnRNP A1 dysfunction correlated with demyelination. We also found that hnRNP A1 dysfunction was induced by IFNγ, indicating that inflammation influences hnRNP A1 function. To fully understand the effects of hnRNP A1 dysfunction on OLs, we performed siRNA knockdown of hnRNP A1, followed by RNA sequencing. RNA sequencing detected over 4000 differentially expressed transcripts revealing alterations to RNA metabolism, cell morphology, and programmed cell death pathways. We confirmed that hnRNP A1 knockdown was detrimental to OLs and induced apoptosis and necroptosis. Together, these data demonstrate a critical role for hnRNP A1 in proper OL functioning and survival and suggest a potential mechanism of OL damage and death in MS that involves hnRNP A1 dysfunction., (© 2022 Wiley Periodicals LLC.)
- Published
- 2023
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18. Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility.
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Cinato M, Mardani I, Miljanovic A, Drevinge C, Laudette M, Bollano E, Henricsson M, Tolö J, Bauza Thorbrügge M, Levin M, Lindbom M, Arif M, Pacher P, Andersson L, Olofsson CS, Borén J, and Levin MC
- Subjects
- Animals, Humans, Mice, Calcium metabolism, Cardiomegaly genetics, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Heart Failure, Myocytes, Cardiac metabolism, Perilipin-5 metabolism, Calcium Signaling
- Abstract
The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally progresses to heart failure, physiological hypertrophy may be cardioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear whether this response is beneficial. We analyzed RNA-sequencing data from human left ventricle and showed that cardiac PLIN5 expression correlates with up-regulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC- Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca
2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. In situ proximity ligation assay further confirmed the Plin5/SERCA2 interaction. Live imaging showed increases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC- Plin5 versus WT cardiomyocytes. These results identify a role of Plin5 in improving cardiac contractility through enhanced Ca2+ signaling., (© 2023 Cinato et al.)- Published
- 2023
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19. Castration of Male Mice Induces Metabolic Remodeling of the Heart.
- Author
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Svedlund Eriksson E, Johansson I, Mårtensson AKF, Lantero Rodriguez M, Schilperoort M, Kroon J, Kooijman S, Omerovic E, Andersson L, Levin MC, Rensen PCN, and Tivesten Å
- Abstract
Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output, and cardiac index during pharmacological stress with dobutamine in castrated vs sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids toward glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in messenger RNA and protein levels of β-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2022
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20. pH-Dependent Protonation of Histidine Residues Is Critical for Electrostatic Binding of Low-Density Lipoproteins to Human Coronary Arteries.
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Glise L, Rutberg M, Håversen L, Levin MC, Levin M, Jeppsson A, Borén J, and Fogelstrand P
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- Glycosaminoglycans metabolism, Histidine, Humans, Hydrogen-Ion Concentration, Proteoglycans metabolism, Static Electricity, Coronary Vessels metabolism, Lipoproteins, LDL metabolism
- Abstract
Background: The initiating step in atherogenesis is the electrostatic binding of LDL (low-density lipoprotein) to proteoglycan glycosaminoglycans in the arterial intima. However, although proteoglycans are widespread throughout the intima of most coronary artery segments, LDL is not evenly distributed, indicating that LDL retention is not merely dependent on the presence of proteoglycans. We aim to identify factors that promote the interaction between LDL and the vessel wall of human coronary arteries., Methods: We developed an ex vivo model to investigate binding of labeled human LDL to human coronary artery sections without the interference of cellular processes., Results: By staining consecutive sections of human coronary arteries, we found strong staining of sulfated glycosaminoglycans throughout the arterial intima, whereas endogenous LDL deposits were focally distributed. Ex vivo binding of LDL was uniform at all intimal areas with sulfated glycosaminoglycans. However, lowering the pH from 7.4 to 6.5 triggered a 35-fold increase in LDL binding. The pH-dependent binding was abolished by pretreating LDL with diethyl-pyrocarbonate, which blocks the protonation of histidine residues, or cyclohexanedione, which inhibits the positive charge of site B on LDL. Thus, both histidine protonation and site B are required for strong electrostatic LDL binding to the intima., Conclusions: This study identifies histidine protonation as an important component for electrostatic LDL binding to human coronary arteries. Our findings show that the local pH will have a profound impact on LDL's affinity for sulfated glycosaminoglycans, which may influence the retention and accumulation pattern of LDL in the arterial vasculature.
- Published
- 2022
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21. Autoimmunity to a ribonucleoprotein drives neuron loss in multiple sclerosis models.
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Libner CD, Salapa HE, Hutchinson C, Stang TE, Thibault PA, Hammond SA, and Levin MC
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- Animals, Autoimmunity, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Mice, Nerve Degeneration, Neurons metabolism, Ribonucleoproteins, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis metabolism
- Abstract
Neurodegeneration, the progressive loss or damage to neurons and axons, underlies permanent disability in multiple sclerosis (MS); yet its mechanisms are incompletely understood. Recent data indicates autoimmunity to several intraneuronal antigens, including the RNA binding protein (RBP) heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), as contributors to neurodegeneration. We previously showed that addition of anti-hnRNP A1 antibodies, which target the same immunodominant domain of MS IgG, to mice with experimental autoimmune encephalomyelitis (EAE) worsened disease and resulted in an exacerbation of hnRNP A1 dysfunction including cytoplasmic mislocalization of hnRNP A1, stress granule (SG) formation and neurodegeneration in the chronic stages of disease. Because this previous study focused on a singular timepoint during EAE, it is unclear whether anti-hnRNP A1 antibody induced hnRNP A1 dysfunction caused neurodegeneration or was result of it. In the present study, we analyzed in vivo and in vitro models of anti-hnRNP A1 antibody-mediated autoimmunity for markers of hnRNP A1 dysfunction and neurodegeneration over a time course to gain a better understanding of the connection between hnRNP A1 dysfunction and neurodegeneration. Anti-hnRNP A1 antibody treatment resulted in increased neuronal hnRNP A1 mislocalization and nuclear depletion temporally followed by altered RNA expression and SG formation, and lastly an increase in necroptotic signalling and neuronal cell death. Treatment with necrostatin-1s inhibited necroptosis and partially rescued anti-hnRNP A1 antibody-mediated neurodegeneration while clathrin knockdown specifically inhibited anti-hnRNP A1 antibody uptake into neurons. This data identifies a novel antibody-mediated mechanism of neurodegeneration, which may be targeted to inhibit neurodegeneration and prevent permanent neurological decline in persons living with MS., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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22. Knock-Down of Heterogeneous Nuclear Ribonucleoprotein A1 Results in Neurite Damage, Altered Stress Granule Biology, and Cellular Toxicity in Differentiated Neuronal Cells.
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Anees A, Salapa HE, Thibault PA, Hutchinson C, Hammond SA, and Levin MC
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- Animals, Cell Line, Gene Knockdown Techniques, Mice, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Neurites pathology, Neurons pathology, Stress Granules
- Abstract
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA binding protein (RBP) that is localized within neurons and plays crucial roles in RNA metabolism. Its importance in neuronal functioning is underscored from the study of its pathogenic features in many neurodegenerative diseases where neuronal hnRNP A1 is mislocalized from the nucleus to the cytoplasm resulting in loss of hnRNP A1 function. Here, we model hnRNP A1 loss-of-function by siRNA-mediated knock-down in differentiated Neuro-2a cells. Through RNA sequencing (RNA-seq) followed by gene ontology (GO) analyses, we show that hnRNP A1 is involved in important biological processes, including RNA metabolism, neuronal function, neuronal morphology, neuronal viability, and stress granule (SG) formation. We further confirmed several of these roles by showing that hnRNP A1 knock-down results in a reduction of neurite outgrowth, increase in cell cytotoxicity and changes in SG formation. In summary, these findings indicate that hnRNP A1 loss-of-function contributes to neuronal dysfunction and cell death and implicates hnRNP A1 dysfunction in the pathogenesis of neurodegenerative diseases., (Copyright © 2021 Anees et al.)
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- 2021
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23. Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking.
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Andersson L, Cinato M, Mardani I, Miljanovic A, Arif M, Koh A, Lindbom M, Laudette M, Bollano E, Omerovic E, Klevstig M, Henricsson M, Fogelstrand P, Swärd K, Ekstrand M, Levin M, Wikström J, Doran S, Hyötyläinen T, Sinisalu L, Orešič M, Tivesten Å, Adiels M, Bergo MO, Proia R, Mardinoglu A, Jeppsson A, Borén J, and Levin MC
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- Animals, Cardiomegaly, Mice, Receptors, Adrenergic, Glucosyltransferases genetics, Myocytes, Cardiac
- Abstract
Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function., Methods and Results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors., Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2021
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24. Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma.
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Pandita A, Ekstrand M, Bjursten S, Zhao Z, Fogelstrand P, Le Gal K, Ny L, Bergo MO, Karlsson J, Nilsson JA, Akyürek LM, Levin MC, Borén J, Ewald AJ, Mostov KE, and Levin M
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- Aged, Aged, 80 and over, Animals, Female, Heterografts, Humans, Male, Matrix Metalloproteinase 9 metabolism, Melanoma metabolism, Mice, Middle Aged, Neovascularization, Pathologic metabolism, Skin Neoplasms metabolism, Melanoma, Cutaneous Malignant, Melanoma pathology, Neovascularization, Pathologic pathology, Skin Neoplasms pathology
- Abstract
Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor-driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (Braf
CA/+ Ptenf/f Tyr-Cre+/0 -mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, in vitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation in vitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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25. Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons.
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Li M, Hamilton R, Salapa HE, and Levin MC
- Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a significant neurodegenerative component. Dysfunctional RNA-binding proteins (RBPs) are causally linked to neuronal damage and are a feature of MS, including the mislocalization of the RBP heterogeneous nuclear ribonucleoprotein A1 (A1). Here, we show that primary neurons exposed to pro-inflammatory cytokines and anti-A1 antibodies, both characteristic of an MS autoimmune response, displayed increased A1 mislocalization, stress granule formation, and decreased neurite length, a marker of neurodegeneration. These findings illustrate a significant relationship between secreted immune factors, A1 dysfunction, and neuronal damage in a disease-relevant model system.
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- 2021
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26. Testosterone reduces metabolic brown fat activity in male mice.
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Lantero Rodriguez M, Schilperoort M, Johansson I, Svedlund Eriksson E, Palsdottir V, Kroon J, Henricsson M, Kooijman S, Ericson M, Borén J, Ohlsson C, Jansson JO, Levin MC, Rensen PCN, and Tivesten Å
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- Animals, Male, Mice, Mice, Inbred C57BL, Norepinephrine metabolism, Orchiectomy, Adipose Tissue, Brown metabolism, Receptors, Androgen deficiency, Testosterone deficiency
- Abstract
Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.
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- 2021
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27. hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease.
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Thibault PA, Ganesan A, Kalyaanamoorthy S, Clarke JWE, Salapa HE, and Levin MC
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The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins' alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease.
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- 2021
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28. A Tripartite Knowledge Translation Program: Innovative Patient-Centered Approach to Clinical Research Participation for Individuals with Multiple Sclerosis.
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Saini A, Cochran C, Zucker-Levin A, Donkers SJ, Kumar P, Knox KB, MacPherson J, Salapa H, and Levin MC
- Abstract
Background: Knowledge translation (KT) models that represent an individual's perspective are a sign of effective KT. Some common challenges in KT include participant engagement, organization of the team, and time demands of the participants. We implemented a unique tripartite KT program to (1) share current research, (2) inform persons living with multiple sclerosis (pwMS) about the clinical research process, and (3) invite pwMS to immediately participate in clinical research. The primary aim was to determine participants' perspectives on the value and acceptability of an experiential research program offered at a patient and family educational conference., Methods: A team of researchers identified factors that would impact the logistics of hosting an experiential research program at a conference and designed a unique tripartite KT program. The local multiple sclerosis (MS) society was engaged to select an appropriate location and invite stakeholders to the conference. A survey to determine participants' perspectives on the value and acceptability of the experiential research program was developed and analyzed., Results: 65 pwMS attended the conference, and 44 (67.7%) participated in the on-site experiential research program. 72.7% of the participants completed the survey, of which 93.8% stated that they strongly agree or agree with the following statements: "Did you feel like participating in research today was a valuable experience to you?" and "Did you feel like you were contributing to MS research?" 100% of the participants agreed or strongly agreed when asked "would you like to see more research activities taking place at these kinds of events?", Conclusions: This paper describes the logistics and challenges of conducting an experiential KT program, which proved to be rewarding for pwMS. The majority of pwMS attending the conference agreed to participate in the on-site experiential research program and an overwhelming majority of participants felt the experience was valuable., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Aman Saini et al.)
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- 2021
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29. A Descriptive Correlational Study to Evaluate Three Measures of Assessing Upper Extremity Function in Individuals with Multiple Sclerosis.
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Saini A, Zucker-Levin A, McMillan B, Kumar P, Donkers S, and Levin MC
- Abstract
Background: Activities of daily living and quality of life (QOL) are hindered by upper extremity (UE) impairments experienced by individuals with multiple sclerosis (iMS). The Nine-Hole Peg Test (9-HPT) is most frequently used to measure UE function. However, it does not measure peoples' ability to perform routine tasks in daily life and may not be useful in iMS who cannot pick up the pegs utilized in the 9-HPT. Therefore, we evaluated three measures to explore a more comprehensive assessment of UE function: Upper Extremity Function Scale (UEFS), Action Research Arm Test (ARAT), and the 9-HPT. The objectives were to quantitatively assess the relationship between these measures of UE function, understand if the measures correlate with QOL as calculated by the MS Quality of Life-54 (MSQOL-54), and to determine differences in the measures based on employment status., Methods: 112 (79 female) iMS were prospectively recruited for this descriptive correlational study. Inclusion criteria were as follows: confirmed diagnosis of MS or clinically isolated syndrome, age ≥ 18 years, and ability to self-consent. All statistical analyses including Spearman's correlation coefficient ( r
s ) and Kruskal-Wallis tests were performed using SPSS., Results: A moderate correlation ( rs = -0.51; p < 0.001) was found between the ARAT and 9-HPT scores for the more impaired hand. Likewise, a moderate correlation was found between UEFS and the physical health composite scores (PHCSs) of MSQOL-54 ( rs = -0.59; p < 0.001). Finally, performances on ARAT, 9-HPT, and UEFS differed between the employed individuals and those on long-term disability ( p = 0.007, p < 0.001, and p = 0.001)., Conclusion: The UEFS moderately correlated with the QOL measure, and considering the UESF is a patient-reported outcome, it could be used to complement routinely captured measures of assessing UE function. Further study is warranted to determine which measure, or combination of measures, is more sensitive to changes in UE function over time., Competing Interests: Dr. Levin has received educational and/or consulting funding from Biogen Idec, Pendopharm, and Sanofi Genzyme. Dr. Zucker-Levin, Dr. Saini, Dr. Donkers, Benjamin McMillan, and Pawan Kumar have no conflicts of interest., (Copyright © 2021 Aman Saini et al.)- Published
- 2021
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30. Diagnostic Dilemma: An Atypical Case of Astrocytoma in a Patient with Relapsing-Remitting Multiple Sclerosis.
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Kahovec C, Saini A, and Levin MC
- Abstract
Distinguishing between tumefactive demyelinating lesions (TDLs) and brain tumors in multiple sclerosis (MS) can be challenging. A progressive course is highly common with brain tumors in MS and no single neuroimaging technique is foolproof when distinguishing between the two. We report a case of a 41-year-old female with relapsing-remitting multiple sclerosis, who had a suspicious lesion within the left frontal hemisphere, without a progressive course. The patient experienced paresthesias primarily to her right hand but remained stable without any functional decline and new neurological symptoms over the four years she was followed. The lesion was followed with brain magnetic resonance imaging (MRI) scans, positron emission tomography-computed tomography scans, and magnetic resonance spectroscopy. Together, these scans favored the diagnosis of a TDL, but a low-grade tumor was difficult to rule out. Examination of serial brain MRI scans showed an enlarging lesion in the left middle frontal gyrus involving the deep white matter. Neurosurgery was consulted and an elective left frontal awake craniotomy was performed. Histopathology revealed a grade II astrocytoma. This case emphasizes the importance of thorough and continuous evaluation of atypical MRI lesions in MS and contributes important features to the literature for timely diagnosis and treatment of similar cases.
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- 2021
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31. A Comprehensive Analysis of the Role of hnRNP A1 Function and Dysfunction in the Pathogenesis of Neurodegenerative Disease.
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Clarke JP, Thibault PA, Salapa HE, and Levin MC
- Abstract
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a member of the hnRNP family of conserved proteins that is involved in RNA transcription, pre-mRNA splicing, mRNA transport, protein translation, microRNA processing, telomere maintenance and the regulation of transcription factor activity. HnRNP A1 is ubiquitously, yet differentially, expressed in many cell types, and due to post-translational modifications, can vary in its molecular function. While a plethora of knowledge is known about the function and dysfunction of hnRNP A1 in diseases other than neurodegenerative disease (e.g., cancer), numerous studies in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, multiple sclerosis, spinal muscular atrophy, Alzheimer's disease, and Huntington's disease have found that the dysregulation of hnRNP A1 may contribute to disease pathogenesis. How hnRNP A1 mechanistically contributes to these diseases, and whether mutations and/or altered post-translational modifications contribute to pathogenesis, however, is currently under investigation. The aim of this comprehensive review is to first describe the background of hnRNP A1, including its structure, biological functions in RNA metabolism and the post-translational modifications known to modify its function. With this knowledge, the review then describes the influence of hnRNP A1 in neurodegenerative disease, and how its dysfunction may contribute the pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Clarke, Thibault, Salapa and Levin.)
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- 2021
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32. Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation.
- Author
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Clarke JWE, Thibault PA, Salapa HE, Kim DE, Hutchinson C, and Levin MC
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- Amyotrophic Lateral Sclerosis pathology, Cytoplasm genetics, Cytoplasm metabolism, Humans, Multiple Sclerosis pathology, Mutation genetics, Amyotrophic Lateral Sclerosis genetics, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Multiple Sclerosis genetics, Nerve Degeneration genetics
- Abstract
Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.
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- 2021
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33. Magnetic Resonance Imaging of Spinal Cord Lesions in Patients with Multiple Sclerosis in Saskatchewan, Canada.
- Author
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Saini A, Bach K, Poliakov I, Knox KB, and Levin MC
- Abstract
Background: Spinal cord lesions (SCLs) contribute to disability in multiple sclerosis (MS). Data in Saskatchewan, Canada, concerning SCLs and their association with disability levels in patients with MS are lacking. The study objectives were to identify clinicodemographic profiles of patients with MS with respect to spinal cord magnetic resonance imaging (MRI) involvement; determine the frequency of individuals with MRI SCLs; and explore differences between patients with MS with and without SCLs with respect to disability and disease-modifying therapy status., Methods: A monocentric, cross-sectional, retrospective review of prospectively collected data from 532 research-consented patients seen at Saskatoon MS Clinic was performed. Data were collected from a database and electronic medical records., Results: Of the 356 patients (66.9%) with an SCL, 180 (50.6%) had only cervical cord lesions. Median Expanded Disability Status Scale (EDSS), ambulation, and pyramidal scores of patients with SCLs were higher than those of patients without SCLs. Of patients with EDSS scores of at least 6, those with SCLs were younger than those without SCLs ( P = .01). Patients with SCLs were 55% less likely to have been on continuous disease-modifying therapy since diagnosis than patients without SCLs (adjusted odds ratio, 0.45; 95% CI, 0.25-0.81; P = .008)., Conclusions: Prevalence and association with disability of SCLs in patients with MS are comparable with existing literature. Patients with MS with SCLs have higher levels of disability and attain EDSS scores of at least 6 at a younger age., Competing Interests: Financial Disclosures: Dr Poliakov has received educational and/or consulting funding from Biogen, Sanofi Genzyme, Teva, Roche, and EMD Serono. Dr Knox is the primary investigator for the Saskatchewan MS Drugs Research Program funded by the Saskatchewan Ministry of Health and is a member of the Saskatchewan MS Drugs review panel for the Saskatchewan Ministry of Health; she has also received funding from the Canadian Institute for Health Information for participation in the former Canadian MS Monitoring System. Dr Levin has received educational and/or consulting funding from Biogen, PendoPharm, and Sanofi Genzyme. The other authors declare no conflicts of interest., (© 2021 Consortium of Multiple Sclerosis Centers.)
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- 2021
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34. Lipid profiling of human diabetic myocardium reveals differences in triglyceride fatty acyl chain length and degree of saturation.
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Björnson E, Östlund Y, Ståhlman M, Adiels M, Omerovic E, Jeppsson A, Borén J, and Levin MC
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- Heart, Humans, Lipid Metabolism, Myocardium metabolism, Triglycerides metabolism, Diabetes Mellitus, Type 2 metabolism
- Abstract
Background: Type 2 diabetes is a major health problem in the world, and is strongly associated with impaired cardiac function and increased mortality. The causal relationship between type 2 diabetes and impaired cardiac function is still incompletely understood but changes in the cardiac lipid metabolism are believed to be a contributing factor. The objective of this study was to determine the lipid profile in human myocardial biopsies collected in vivo from patients with type 2 diabetes and compare to non-diabetic controls., Method: We conducted full lipidomics analyses, using mass spectrometry, of 85 right atrial biopsies obtained from diabetic and non-diabetic patients undergoing elective cardiac surgery. The patients were characterized clinically and serum was analyzed for lipids and biochemical markers., Results: The groups did not differ in BMI and in circulating triglycerides. We demonstrate that type 2 diabetes is associated with alterations in the cardiac lipidome. Interestingly, the absolute amount of lipids is not altered in the diabetic myocardium. However, triglycerides with longer fatty acyl chains are more abundant and there is a higher degree of unsaturated fatty acid chains in triglycerides in diabetic myocardium., Conclusions: Our study reveals that type 2 diabetes is a relatively strong determinant of the human cardiac lipidome (compared to other clinical variables). Although the total lipid content in the diabetic myocardium is not increased, the lipid composition is markedly affected., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)
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- 2020
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35. Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations.
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Freedman MS, Devonshire V, Duquette P, Giacomini PS, Giuliani F, Levin MC, Montalban X, Morrow SA, Oh J, Rotstein D, and Yeh EA
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- Canada epidemiology, Humans, Immunosuppressive Agents therapeutic use, Magnetic Resonance Imaging methods, Magnetic Resonance Imaging standards, Multiple Sclerosis diagnostic imaging, Treatment Outcome, Multiple Sclerosis drug therapy, Multiple Sclerosis epidemiology, Practice Guidelines as Topic standards
- Abstract
The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.
- Published
- 2020
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36. Neuronal RNA-binding protein dysfunction in multiple sclerosis cortex.
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Salapa HE, Hutchinson C, Popescu BF, and Levin MC
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Multiple Sclerosis pathology, Neurons classification, Cerebral Cortex metabolism, DNA-Binding Proteins metabolism, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Multiple Sclerosis metabolism, Neurons metabolism, RNA-Binding Proteins metabolism
- Abstract
Objective: Neurodegeneration is thought to be the primary cause of neurological disability in multiple sclerosis (MS). Dysfunctional RNA-binding proteins (RBPs) including their mislocalization from nucleus to cytoplasm, stress granule formation, and altered RNA metabolism have been found to underlie neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia. Yet, little is known about the role of dysfunctional RBPs in the pathogenesis of neurodegeneration in MS. As a follow-up to our seminal finding of altered RBP function in a single case of MS, we posited that there would be evidence of RBP dysfunction in cortical neurons in MS., Methods: Cortical neurons from 12 MS and six control cases were analyzed by immunohistochemistry for heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA-binding protein-43 (TDP-43). Seven distinct neuronal phenotypes were identified based on the nucleocytoplasmic staining of these RBPs. Statistical analyses were performed by analyzing each phenotype in relation to MS versus controls., Results: Analyses revealed a continuum of hnRNP A1 and TDP-43 nucleocytoplasmic staining was found in cortical neurons, from neurons with entirely nuclear staining with little cytoplasmic staining in contrast to those with complete nuclear depletion of RBPs concurrent with robust cytoplasmic staining. The neuronal phenotypes that showed the most nucleocytoplasmic mislocalization of hnRNP A1 and TDP-43 statistically distinguished MS from control cases (P < 0.01, P < 0.001, respectively)., Interpretation: The discovery of hnRNP A1 and TDP-43 nucleocytoplasmic mislocalization in neurons in MS brain demonstrate that dysfunctional RBPs may play a role in neurodegeneration in MS, as they do in other neurological diseases., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2020
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37. Antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 contribute to neuronal cell loss in an animal model of multiple sclerosis.
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Libner CD, Salapa HE, Hutchinson C, Lee S, and Levin MC
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- Animals, Autoantigens immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Mice, Mice, Inbred C57BL, Multiple Sclerosis, Neurons immunology, Autoantibodies immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Heterogeneous Nuclear Ribonucleoprotein A1 immunology, Nerve Degeneration immunology, Neurons pathology
- Abstract
Neurodegeneration, including loss of neurons and axons, is a feature of progressive forms of multiple sclerosis (MS). The mechanisms underlying neurodegeneration are mostly unknown. Research implicates autoimmunity to nonmyelin self-antigens as important contributors to disease pathogenesis. Data from our lab implicate autoimmunity to the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a possible mechanism of neurodegeneration in MS. MS patients make antibodies to hnRNP A1, which have been shown to lead to neuronal dysfunction in vitro. Using an animal model of MS, experimental autoimmune encephalomyelitis (EAE), we show here that injection of anti-hnRNP A1 antibodies, in contrast to control antibodies, resulted in worsened disease and increased neurodegeneration. We found a reduction of NeuN
+ neuronal cell bodies in areas of the ventral gray matter of the spinal cord where anti-hnRNP A1 antibodies localized. Neurons displayed increased levels of hnRNP A1 nucleocytoplasmic mislocalization and stress granule formation, both markers of neuronal injury. Anti-hnRNP A1 antibodies were found to surround neuronal cell bodies and interact with CD68+ immune cells via Fc receptors. Additionally, anti-hnRNP A1 antibodies were found within neuronal cell bodies including those of the ventral spinocerebellar tract (VSCT), a tract previously shown to undergo neurodegeneration in anti-hnRNP A1 antibody injected EAE mice. Finally, both immune cells and neurons showed increased levels of inducible nitric oxide synthase, another indicator of cell damage. These findings suggest that autoimmunity to RBPs, such as hnRNP A1, play a role in neurodegeneration in EAE with important implications for the pathogenesis of MS., (© 2019 Wiley Periodicals, Inc.)- Published
- 2020
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38. The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models.
- Author
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Libner CD, Salapa HE, and Levin MC
- Subjects
- Animals, Disease Progression, Humans, Neurodegenerative Diseases etiology, Neurodegenerative Diseases metabolism, Oxidative Stress, Multiple Sclerosis complications, Neurodegenerative Diseases pathology, RNA-Binding Proteins metabolism
- Abstract
Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs., Competing Interests: The other declares no conflict of interest.
- Published
- 2020
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39. Dysfunctional RNA-binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice.
- Author
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Salapa HE, Libner CD, and Levin MC
- Subjects
- Animals, DNA-Binding Proteins metabolism, Female, Gray Matter metabolism, Gray Matter pathology, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Mice, Inbred C57BL, Multiple Sclerosis metabolism, Multiple Sclerosis pathology, Neurons metabolism, Neurons pathology, Stress, Physiological, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, RNA-Binding Proteins metabolism, Spinal Cord metabolism, Spinal Cord pathology
- Abstract
Altered stress granule (SG) and RNA-binding protein (RBP) biology have been shown to contribute to the pathogenesis of several neurodegenerative diseases, yet little is known about their role in multiple sclerosis (MS). Pathological features associated with dysfunctional RBPs include RBP mislocalization from its normal nuclear location to the cytoplasm and the formation of chronic SGs. We tested the hypothesis that altered SG and RBP biology might contribute to the neurodegeneration in experimental autoimmune encephalomyelitis (EAE). C57BL/6 female mice were actively immunized with MOG
35-55 to induce EAE. Spinal cords were examined for mislocalization of the RBPs, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA binding protein-43 (TDP-43), SGs, neurodegeneration (SMI-32), T cells (CD3), and macrophages (CD68). In contrast to naive mice, mice with EAE showed SG formation (p < 0.0001) and mislocalization of hnRNP A1 (p < 0.05) in neurons of the ventral spinal cord gray matter, which correlated with clinical score (R = 0.8104, p = 0.0253). In these same areas, there was a neuronal loss (p < 0.0001) and increased SMI-32 immunoreactivity (both markers of neurodegeneration) and increased staining for CD3+ T cells and IFN-gamma. These findings recapitulate the SG and RBP biology and markers of neurodegeneration in MS tissues and suggest that altered SG and RBP biology contribute to the neurodegeneration in EAE, which might also apply to the pathogenesis of MS., (© 2019 Wiley Periodicals, Inc.)- Published
- 2020
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40. The Dilemma of When to Stop Disease-Modifying Therapy in Multiple Sclerosis: A Narrative Review and Canadian Regional Reimbursement Policies.
- Author
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Knox KB, Saini A, and Levin MC
- Abstract
Background: Disease-modifying therapy (DMT) has changed the landscape of multiple sclerosis (MS) care. However, there is lack of consensus on the duration of treatment and the selection of individuals most likely to benefit from continued treatment. Current evidence, practice guidelines, health policy, and ethical considerations presented together may further inform challenging clinical decision making and future directions. The objectives of this study were to conduct a narrative review of original research and practice guideline recommendations on discontinuation of DMTs in MS; to collect information regarding Canadian regional reimbursement policies for DMT coverage in MS; and to present ethical considerations applicable to such decision making., Methods: A literature review was conducted of the MEDLINE/PubMed, OneFile (GALE), Scopus (Elsevier), and ProQuest Biological Science Collection databases. Data regarding Canadian regional reimbursement policies for DMT coverage in MS were collected from the ministry/government websites. Ethical considerations were reviewed in the context of the identified evidence, guidelines, and policies., Results: The literature lacks evidence from prospective randomized controlled trials that directly addresses the issue of discontinuation of DMTs in MS. Current practice guidelines advocate the vital role of patient choice in decision making. There are regional variations in Expanded Disability Status Scale criteria scores for continuing MS DMT coverage among Canadian provinces/territories., Conclusions: In the absence of strong evidence on discontinuation of DMTs, shared decision making and consideration of the ethical complexities could help in the decision-making process., Competing Interests: Dr Knox is the primary investigator for the Saskatchewan MS Drugs Research Program funded by the Saskatchewan Ministry of Health, is a member of the Saskatchewan MS Drugs review panel for the Saskatchewan Ministry of Health, and has received funding from the Canadian Institute for Health Information for participation in the former Canadian MS Monitoring System. Dr Levin has received educational and/or consulting funding from Biogen, Pendopharm, and Sanofi Genzyme. Dr Saini declares no conflicts of interest., (© 2020 Consortium of Multiple Sclerosis Centers.)
- Published
- 2020
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41. Individualised behaviour change strategies for physical activity in multiple sclerosis (IPAC-MS): protocol for a randomised controlled trial.
- Author
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Goulding FL, Evans CD, Knox KB, Lim HJ, Levin MC, and Donkers SJ
- Subjects
- Female, Humans, Male, Outcome Assessment, Health Care, Self Report, Single-Blind Method, Surveys and Questionnaires, Exercise, Multiple Sclerosis psychology, Randomized Controlled Trials as Topic
- Abstract
Background: Multiple sclerosis (MS) is a chronic, degenerative disease of the central nervous system. Because of the long-term and unpredictable nature of the disease, the burden of MS is significant from both a patient and societal perspective. Despite a recent influx of disease-modifying therapies to treat MS, many individuals continue to experience disability that negatively affects productivity and quality of life. Previous research indicates that physical activity has a positive impact on walking function in individuals with MS, in addition to the usual beneficial effects on overall health. However, most people with MS are not active enough to gain these benefits, and a lack of support to initiate and maintain physical activity has been identified as a major barrier. This study will evaluate the impact of a novel intervention involving individualised behaviour change strategies delivered by neurophysiotherapists on increasing physical activity levels in individuals with MS who are currently inactive., Methods/design: This single-blind, parallel-group, randomised controlled trial will be conducted in Saskatchewan, Canada. Eligible participants include individuals with MS who are ambulatory but identified as currently inactive by the self-reported Godin Leisure-Time Exercise Questionnaire (GLTEQ). The intervention will be delivered by neurophysiotherapists and includes individualised behaviour change strategies aimed at increasing physical activity over a 12-month period. The control group will receive usual care during the 12-month study period. The primary outcome is the change in physical activity level, as measured by the change in the GLTEQ score from baseline to 12 months. Secondary outcomes include the change in patient-reported outcome measures assessing MS-specific symptoms, confidence and quality of life., Discussion: Physical activity has been identified as a top research priority by the MS community. Findings from this novel study may result in new knowledge that could significantly impact the management and overall health of individuals with MS., Trial Registration: ClinicalTrials.gov, NCT04027114. Registered on 10 July 2019.
- Published
- 2019
- Full Text
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42. Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.
- Author
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Mardani I, Tomas Dalen K, Drevinge C, Miljanovic A, Ståhlman M, Klevstig M, Scharin Täng M, Fogelstrand P, Levin M, Ekstrand M, Nair S, Redfors B, Omerovic E, Andersson L, Kimmel AR, Borén J, and Levin MC
- Subjects
- Animals, Cell Respiration, Heart physiology, Male, Mice, Mice, Inbred C57BL, Mitochondria metabolism, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, Triglycerides metabolism, Autophagy, Lipid Metabolism, Myocardium cytology, Myocardium metabolism, Perilipin-2 deficiency
- Abstract
Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2
-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.- Published
- 2019
- Full Text
- View/download PDF
43. Stabilization Without Rituximab After Disease Activation in an Alemtuzumab-Treated Patient with Multiple Sclerosis and a Literature Overview.
- Author
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Kahovec C and Levin MC
- Abstract
There has been an increasing number of reports describing B-cell-associated disease activation in patients with multiple sclerosis after alemtuzumab treatment. Herein, 4.5 months after a first alemtuzumab infusion, a 33-year-old female patient had altered gait and vision loss associated with gadolinium enhancement of the optic nerves and chiasm on brain magnetic resonance imaging. The patient's blood showed normal B-cell counts concurrent with abnormally low T-cell counts. The patient stabilized after receiving steroids and prolonged plasma exchange without the use of rituximab. This case report adds to the growing body of literature of B-cell-associated disease activation after alemtuzumab infusion and provides a therapeutic strategy to stabilize patients when rituximab is not readily available or if contraindications to its use exist., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2019
- Full Text
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44. Localization of near-infrared labeled antibodies to the central nervous system in experimental autoimmune encephalomyelitis.
- Author
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Lee S, Salapa HE, and Levin MC
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Blood-Brain Barrier metabolism, Brain diagnostic imaging, Central Nervous System metabolism, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Fluorescent Dyes chemistry, Heterogeneous Nuclear Ribonucleoprotein A1 immunology, Matrix Metalloproteinases metabolism, Mice, Mice, Inbred C57BL, Spinal Cord diagnostic imaging, Antibodies, Monoclonal immunology, Central Nervous System diagnostic imaging, Encephalomyelitis, Autoimmune, Experimental pathology, Spectroscopy, Near-Infrared
- Abstract
Antibodies, including antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1, have been shown to contribute to the pathogenesis of multiple sclerosis, thus it is important to assess their biological activity using animal models of disease. Near-infrared optical imaging of fluorescently labeled antibodies and matrix metalloproteinase activity were measured and quantified in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. We successfully labeled, imaged and quantified the fluorescence signal of antibodies that localized to the central nervous system of mice with experimental autoimmune encephalomyelitis. Fluorescently labeled anti-heterogeneous nuclear ribonucleoprotein A1 antibodies persisted in the central nervous system of mice with experimental autoimmune encephalomyelitis, colocalized with matrix metalloproteinase activity, correlated with clinical disease and shifted rostrally within the spinal cord, consistent with experimental autoimmune encephalomyelitis being an ascending paralysis. The fluorescent antibody signal also colocalized with matrix metalloproteinase activity in brain. Previous imaging studies in experimental autoimmune encephalomyelitis analyzed inflammatory markers such as cellular immune responses, dendritic cell activity, blood brain barrier integrity and myelination, but none assessed fluorescently labeled antibodies within the central nervous system. This data suggests a strong association between autoantibody localization and disease. This system can be used to detect other antibodies that might contribute to the pathogenesis of autoimmune diseases of the central nervous system including multiple sclerosis., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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- View/download PDF
45. Dysfunctional RNA binding proteins and stress granules in multiple sclerosis.
- Author
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Salapa HE, Johnson C, Hutchinson C, Popescu BF, and Levin MC
- Subjects
- Cell Line, Tumor, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Humans, Male, Middle Aged, Multiple Sclerosis genetics, Multiple Sclerosis pathology, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Multiple Sclerosis metabolism, Oxidative Stress physiology
- Abstract
Dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonuclear protein A1 (hnRNP A1) has been shown to contribute to the pathogenesis of neurodegenerative diseases, but its involvement in multiple sclerosis (MS) is largely unknown. In a neuronal cell line, interferon-γ caused hnRNP A1 nucleocytoplasmic mislocalization; colocalization of hnRNP A1 in stress granules (SGs); and inhibition of translation. Neurons in the brain of a MS patient showed pathogenic RBP dysfunction, including nuclear depletion of hnRNP A1, its mislocalization to the cytoplasm, and its colocalization in SGs. These data indicate a role for dysfunctional hnRNP A1 in the pathogenesis of MS., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2018
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- View/download PDF
46. Deficiency in perilipin 5 reduces mitochondrial function and membrane depolarization in mouse hearts.
- Author
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Andersson L, Drevinge C, Mardani I, Dalen KT, Ståhlman M, Klevstig M, Lundqvist A, Haugen F, Adiels M, Fogelstrand P, Asin-Cayuela J, Hultén LM, Levin M, Ehrenborg E, Lee YK, Kimmel AR, Borén J, and Levin MC
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Membrane Potential, Mitochondrial, Mitochondria metabolism, Myocytes, Cardiac cytology, Perilipin-5 deficiency
- Abstract
Myocardial triglycerides stored in lipid droplets are important in regulating the intracellular delivery of fatty acids for energy generation in mitochondria, for membrane biosynthesis, and as agonists for intracellular signaling. Previously, we showed that deficiency in the lipid droplet protein perilipin 5 (Plin5) markedly reduces triglyceride storage in cardiomyocytes and increases the flux of fatty acids into phospholipids. Here, we investigated whether Plin5 deficiency in cardiomyocytes alters mitochondrial function. We found that Plin5 deficiency reduced mitochondrial oxidative capacity. Furthermore, in mitochondria from Plin5
-/ - - Published
- 2017
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47. Contribution of the Degeneration of the Neuro-Axonal Unit to the Pathogenesis of Multiple Sclerosis.
- Author
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Salapa HE, Lee S, Shin Y, and Levin MC
- Abstract
Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. In recent years, it has become more evident that neurodegeneration, including neuronal damage and axonal injury, underlies permanent disability in MS. This manuscript reviews some of the mechanisms that could be responsible for neurodegeneration and axonal damage in MS and highlights the potential role that dysfunctional heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and antibodies to hnRNP A1 may play in MS pathogenesis., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2017
- Full Text
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48. Depletion of ATP and glucose in advanced human atherosclerotic plaques.
- Author
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Ekstrand M, Widell E, Hammar A, Akyürek LM, Johansson M, Fagerberg B, Bergström G, Levin MC, Fogelstrand P, Borén J, and Levin M
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Adenosine Triphosphate metabolism, Glucose metabolism, Plaque, Atherosclerotic metabolism
- Abstract
Objective: Severe hypoxia develops close to the necrotic core of advanced human atherosclerotic plaques, but the energy metabolic consequences of this hypoxia are not known. In animal models, plaque hypoxia is also associated with depletion of glucose and ATP. ATP depletion may impair healing of plaques and promote necrotic core expansion. To investigate if ATP depletion is present in human plaques, we analyzed the distribution of energy metabolites (ATP, glucose, glycogen and lactate) in intermediate and advanced human plaques., Approach and Results: Snap frozen carotid endarterectomies from 6 symptomatic patients were analyzed. Each endarterectomy included a large plaque ranging from the common carotid artery (CCA) to the internal carotid artery (ICA). ATP, glucose, and glycogen concentrations were lower in advanced (ICA) compared to intermediate plaques (CCA), whereas lactate concentrations were higher. The lowest concentrations of ATP, glucose and glycogen were detected in the perinecrotic zone of advanced plaques., Conclusions: Our study demonstrates severe ATP depletion and glucose deficiency in the perinecrotic zone of human advanced atherosclerotic plaques. ATP depletion may impair healing of plaques and promote disease progression.
- Published
- 2017
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49. Autoantibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNPA1) cause altered 'ribostasis' and neurodegeneration; the legacy of HAM/TSP as a model of progressive multiple sclerosis.
- Author
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Levin MC, Lee S, Gardner LA, Shin Y, Douglas JN, and Salapa H
- Subjects
- Animals, Heterogeneous Nuclear Ribonucleoprotein A1, Humans, Multiple Sclerosis, Chronic Progressive pathology, Neurodegenerative Diseases immunology, Neurodegenerative Diseases pathology, Paraparesis, Tropical Spastic pathology, Autoantibodies immunology, Heterogeneous-Nuclear Ribonucleoprotein Group A-B immunology, Multiple Sclerosis, Chronic Progressive immunology, Paraparesis, Tropical Spastic immunology
- Abstract
Several years following its discovery in 1980, infection with human T-lymphotropic virus type 1 (HTLV-1) was shown to cause HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease biologically similar to progressive forms of multiple sclerosis (MS). In this manuscript, we review some of the clinical, pathological, and immunological similarities between HAM/TSP and MS with an emphasis on how autoantibodies to an RNA binding protein, heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), might contribute to neurodegeneration in immune mediated diseases of the central nervous system., (Published by Elsevier B.V.)
- Published
- 2017
- Full Text
- View/download PDF
50. Perilipin 5 is protective in the ischemic heart.
- Author
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Drevinge C, Dalen KT, Mannila MN, Täng MS, Ståhlman M, Klevstig M, Lundqvist A, Mardani I, Haugen F, Fogelstrand P, Adiels M, Asin-Cayuela J, Ekestam C, Gådin JR, Lee YK, Nebb H, Svedlund S, Johansson BR, Hultén LM, Romeo S, Redfors B, Omerovic E, Levin M, Gan LM, Eriksson P, Andersson L, Ehrenborg E, Kimmel AR, Borén J, and Levin MC
- Subjects
- Animals, Coronary Artery Disease blood, Coronary Artery Disease genetics, Coronary Artery Disease prevention & control, Female, Humans, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Mice, Knockout, Muscle Proteins genetics, Myocardial Ischemia genetics, Myocardium metabolism, Myocardium pathology, Triglycerides blood, Intracellular Signaling Peptides and Proteins deficiency, Muscle Proteins deficiency, Myocardial Ischemia blood, Myocardial Ischemia prevention & control
- Abstract
Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia., Methods and Results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction., Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
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