277 results on '"Ahmet, Hoke"'
Search Results
2. 48. Igf-1 Nanoparticles In A Nanofiber Hydrogel-based Drug Delivery System Enhance Functional Recovery In Non-human Primatesfollowing Peripheral Nerve Injury
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Tom Harris, MD, William Padovano, MD, Chenhu Qiu, PhD, Visakha Suresh, MD, Pierce Perkins, BS, Mark Poisler, BS, Erica Lee, MS, Karim Sarhane, MD, Philip Hanwright, MD, Ahmet Hoke, MD, Kara Segna, MD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2024
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3. Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury
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Andrés Fuentes‐Flores, Cristian Geronimo‐Olvera, Karina Girardi, David Necuñir‐Ibarra, Sandip Kumar Patel, Joanna Bons, Megan C Wright, Daniel Geschwind, Ahmet Hoke, Jose A Gomez‐Sanchez, Birgit Schilling, Daniela L Rebolledo, Judith Campisi, and Felipe A Court
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aging ,chronic denervation ,nerve regeneration ,Schwann cell ,senescence ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c‐Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c‐Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c‐Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c‐Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.
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- 2023
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4. Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis
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Ye Eun Jeong, Labchan Rajbhandari, Byung Woo Kim, Arun Venkatesan, and Ahmet Hoke
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long‐term neurological disabilities that are not amenable to current immunomodulatory therapies. Methods and Results Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)‐induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury‐response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Interpretation Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.
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- 2023
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5. 60. Insulin Like Growth Factor 1 Nanoparticle Based Drug Delivery System for Peripheral Nerve Injury in Non-human Primates
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Thomas Harris, MBChB, William Padovano, MD, Chenhu Qiu, BS, Visakha Suresh, MD, Pierce Perkins, BS, Mark Poisler, NA Erica Lee, MS, Karim Sarhane, MD, Philip Hanwright, MD, Kara Segna, MD, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2023
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6. 15. Sustained Agrin Nanoparticle Delivery Improves Neuromuscular Junction Reinnervation and Functional Recovery after Chronic Denervation
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Erica Lee, MS, Chenhu Qiu, BS, Thomas Harris, MBChB, Visakha Suresh, MD, William Padovano, MD, Hafsa Omer Sulaiman, BS, Rachana Suresh, MBBS, Alyssa Lee, BS, Nicholas von Guionneau, MBBS, Zohra Aslami, BS, Yicheng Zhang, BS, Zhicheng Yao, MS, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2023
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7. D20. Agrin Nanoparticles in a Nanofiber Hydrogel-based Drug Delivery System Improve Neuromuscular Junction Reinnervation following Chronic Denervation
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Erica Lee, MS, Chenhu Qiu, BS, Thomas Harris, MBChB, Visakha Suresh, MD, William Padovano, MD, Hafsa Omer Sulaiman, BS, Rachana Suresh, MBBS, Alyssa Lee, BS, Nicholas von Guionneau, MBBS, Zohra Aslami, BS, Yicheng Zhang, BS, Zhicheng Yao, MS, Ahmet Hoke, MD PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2023
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8. Ethoxyquin is neuroprotective and partially prevents somatic and autonomic neuropathy in db/db mouse model of type 2 diabetes
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Ying Liu, Yuan Sun, Osefame Ewaleifoh, Josh Wei, Ruifa Mi, Jing Zhu, Ahmet Hoke, and Michael Polydefkis
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Medicine ,Science - Abstract
Abstract Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.
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- 2021
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9. Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration
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Na Zhang, Ulla Milbreta, Jiah Shin Chin, Coline Pinese, Junquan Lin, Hitomi Shirahama, Wei Jiang, Hang Liu, Ruifa Mi, Ahmet Hoke, Wutian Wu, and Sing Yian Chew
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Science - Published
- 2022
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10. Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation
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Aysel Cetinkaya-Fisgin, Xinghua Luan, Nicole Reed, Ye Eun Jeong, Byoung Chol Oh, and Ahmet Hoke
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Medicine ,Science - Abstract
Abstract Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.
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- 2020
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11. Change of guard at ACTN
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Ahmet Hoke
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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12. Sustained Agrin Nanoparticle Delivery Ameliorates Effects of Denervation and Preserves Neuromuscular Junction Morphology after Peripheral Nerve Injury
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Erica Lee, Chenhu Qiu, Tom Harris, Nicholas von Guionneau, Hafsa Omer Sulaiman, Rachana Suresh, Alyssa Lee, Yicheng Zhang, Madi Kusamanov, Zohra Aslami, Matthew Generoso, Ahmet Hoke, Hai-Quan Mao, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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13. P18. A NOVEL BIOENGINEERED CONDUIT REDUCES NEUROMA FORMATION AFTER TARGETED MUSCLE REINNERVATION
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Erica Lee, MS, Bruce Enzmann, BS, Thomas Harris, MBChB, Alison Wong, MD, Sai Pinni, BS, Nicholas von Guionneau, MBBS, Ruchita Kothari, BS, Michael Lan, BME, Chenhu Qiu, BS, Anson Zhou, BME, Alyssa Lee, BS, Jaimie Shores, MD, Alban Latremoliere, MD, Lintao Qu, PhD, Ahmet Hoke, MD PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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14. 101. Agrin Nanoparticles in a Nanofiber Hydrogel-based Drug Delivery System to Reduce Neuromuscular Junction Degradation After Peripheral Nerve Injury
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Erica Lee, MS, Chenhu Qiu, BS, Thomas Harris, MD, Nicholas von Guionneau, MD, Zohra Alsami, BS, Matthew Generoso, BS, Yicheng Zhang, BS, Zhicheng Yao, MS, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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15. QS51. Guiding the Way: The Use of a Bioengineered Conduit Reduces Neuroma Formation and Associated Pain Behaviors
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Erica Lee, MS, Bruce Enzmann, BS, Thomas Harris, MD, Alison Wong, MD, Sai Pinni, BS, Nicholas von Guionneau, MD, Ruchita Kothari, BS, Michael Lan, BME, Chenhu Qiu, BME, Anson Zhou, BME, Jaimie Shores, MD, Alban Latremoliere, MD, Lintao Qu, MD, PhD, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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16. 23. STOPPING THE CLOCK: AGRIN NANOPARTICLE THERAPY REDUCES NEUROMUSCULAR JUNCTION DEGRADATION AFTER PERIPHERAL NERVE INJURY
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Erica B. Lee, MS, Chenhu Qiu, , BS, Thomas G.W. Harris, MBChB, Nicholas von Guionneau, MBBS, Zohra Alsami, BS, Matthew Generoso, BS, Yicheng Zhang, BS, Zhicheng Yao, MS, Ahmet Hoke, MD PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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17. 50. INSULIN LIKE GROWTH FACTOR-1 IMPROVE FUNCTIONAL RECOVERY IN NOVEL RAT AND NON-HUMAN PRIMATE PERIPHERAL NERVE INJURY MODELS
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Thomas Harris, MBChB, Karim Sarhane, MD, Chenhu Qiu, BS, Philip Hanwright, MD, Connor Glass, , MD, Alison Wong, MD, Nicholas von Guionneau, MBBS, Harsha Malapati, BS, Nicholas Hricz, BS, Matthew Generoso, BS, Sai Pinni, BS, Erica Lee, BS, Richard Redett, III, MD, Kara Segna, MD, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Published
- 2022
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18. A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype
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Daisuke, Murata, Christopher, Grunseich, Miho, Iijima, David, Chan, Andrea, Corse, Ahmet, Hoke, Alice, Schindler, Hiromi, Sesaki, and Ricardo H, Roda
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Neurology ,Neurology (clinical) - Abstract
Background: The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. Objective: To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. Methods: We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. Results: We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. Conclusions: The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.
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- 2023
19. QS1: Pre-implanted Nerve Grafts (PING) to Improve Functional Outcomes in VCA
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Nicholas von Guionneau, MBBS, Xiuyun Liu, PhD, Benjamin Slavin, BS, Emily Finkelstein, BS, Joshua Yoon, MD, Erica Lee, BS, Ruchita Kothari, BS, Connor Glass, BS, Kimberly Khoo, BS, Raymond Kohler, PhD, Ahmet Hoke, MD PhD, Jamie Shores, MD, Gerald Brandacher, MD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Abstract
Purpose: Improved graft reinnervation and functional recovery would greatly enhance the utility of vascularized composite allotransplantation (VCA). Pre-implantation of nerve grafts in a limb transplant recipient prior to transplantation to increase the length of the severed nerves in the amputation stump offers a novel, readily translatable approach to this problem. At the time of transplantation a pre-implanted nerve graft (PING) would be elevated from its wound bed in the amputated stump and unfurled distally into the transplanted limb, allowing for a more distal nerve coaptation. Methods: We used a reversed sciatic-tibial nerve isograft coapted end-to-end to a median nerve in a rat to: (1) determine viability of distal axons after elevating PINGs; and (2) assess for ischemic injury to axons in the distal PING following elevation from the wound bed. For axonal viability, grafts of varying lengths (2cm,3cm,4cm, n≥5/group) were left to regenerate for 8 weeks. The distal ends were then biopsied prior to elevation, and again one week after elevation. For ischemia assessment, blood flow along 4cm long PINGs was measured with laser doppler at multiple timepoints: baseline (at time of grafting), 8 weeks after grafting (before elevation), immediately after elevation, and 3 and 7 days post-elevation (n=8/timepoint). Means were compared with t-tests and ANOVA. A pig forelimb model was used to assess the functional impact of PINGs. A 6cm long reversed ulnar-PING was coapted to the proximally transected ulnar nerve. After 12 weeks of regeneration, the distal PING was transferred end-to-end to the median nerve just proximal to the elbow. A control group underwent ulnar-to-median nerve transfer 6cm proximal to the elbow (n=4 limbs/group). Hoof flexion force was measured every three weeks. Results Axonal viability: after 8 weeks, axons had regenerated into the distal grafts in all lengths: mean myelinated axon counts (±SD): 7043 (±790), 6066 (±1838), 6491 (±983) in 2cm,3cm,4cm grafts, with no differences between graft lengths (p=0.48). One week after elevation and unfurling, the number of myelinated axons was significantly decreased in all groups (p
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- 2021
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20. Downregulation of <scp>SF3B2</scp> protects <scp>CNS</scp> neurons in models of multiple sclerosis
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Ye Eun Jeong, Labchan Rajbhandari, Byung Woo Kim, Arun Venkatesan, and Ahmet Hoke
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General Neuroscience ,Neurology (clinical) - Abstract
Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long-term neurological disabilities that are not amenable to current immunomodulatory therapies.Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)-induced mice. By employing an in vitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury-response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration.Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.
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- 2022
21. Kynurenines link chronic inflammation to functional decline and physical frailty
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Reyhan Westbrook, Tae Chung, Jacqueline Lovett, Chris Ward, Humberto Joca, Huanle Yang, Mohammed Khadeer, Jing Tian, Qian-Li Xue, Anne Le, Luigi Ferrucci, Ruin Moaddel, Rafa de Cabo, Ahmet Hoke, Jeremy Walston, and Peter M. Abadir
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Aging ,Inflammation ,Medicine - Abstract
Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.
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- 2020
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22. QS9: Determining the Critical Time of Chronic Schwann Cell Denervation on Functional Recovery and Rna Expression
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Alison L. Wong, MD, MSE, Thomas Harris, MBBS, Connor Glass, BS, Nicholas Nicholas von Guionneau, MBBS, Erica Lee, MS, Nicholas Hricz, BS, Harsha Malapati, BS, Ruifa Mi, MD, PhD, Vivek Swarup, PhD, Riki Kawaguchi, PhD, Ahmet Hoke, MD, PhD, and Sami Tuffaha, MD
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Surgery ,RD1-811 - Abstract
Purpose: There is poor functional recovery following delayed peripheral nerve repair since both muscle and Schwann cells (SC) undergo denervation atrophy. We investigated the specific temporal effect of nerve/SC denervation on recovery as well as changes in RNA expression in the nerves that may elucidate changes in recovery potential. We hypothesized that functional recovery would be worse after prolonged nerve/SC denervation and that the expression profiles would differ. Methods: Our study was conducted using a forelimb model in adult Lewis rats. Each animal underwent unilateral forelimb denervation of 8, 12, 16, or 24 weeks duration. In the functional recovery arm of the study, the ulnar nerve was denervated proximally or a sham surgery was performed. After the denervation period had elapsed, an in situ nerve transfer of median to ulnar to median nerve was performed. Functional recovery was then measured by stimulated grip strength weekly for 12 weeks. In the RNA expression arm, median and ulnar nerves were denervated. The same time points were used with the addition of a 1-week denervation group. After the denervation period, the median and ulnar nerves were harvested bilaterally. To create a comprehensive RNA-Seq dataset, the median nerve, with an average length of 3 cm, was homogenized and RNA was purified. RNA-sequencing was carried out using TrueSeq RiboZero gold kit. Samples were analyzed through FastQC, aligned to reference genome using STAR and quantified as transcripts per million (TPM) using Salmon. Principle component analysis was performed, followed by differential gene analysis using a linear mixed effects model to control for the control nerves being from the same animals. Results: Functional recovery was statistically significantly different depending on the duration of nerve/SC denervation (P0.05, we identified 1624 genes differentially expressed, of which 327 genes were upregulated and rest (1297 genes) downregulated with denervation. Conclusions: Prolonged nerve/SC denervation of more than 12 weeks resulted in significantly worse functional recovery. RNA sequencing demonstrated that not only were there many genes differentially expressed, but these appear to vary with duration of denervation as well. Further investigation into the specific genes and their changes over time will allow us to know why recovery potential is decreased and targets for interventions to improve recovery.
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- 2021
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23. Biomimicking Fiber Scaffold as an Effective In Vitro and In Vivo MicroRNA Screening Platform for Directing Tissue Regeneration
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Na Zhang, Ulla Milbreta, Jiah Shin Chin, Coline Pinese, Junquan Lin, Hitomi Shirahama, Wei Jiang, Hang Liu, Ruifa Mi, Ahmet Hoke, Wutian Wu, and Sing Yian Chew
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contact guidance ,electrospinning ,gene silencing ,neural tissue engineering ,RNA interference ,Science - Abstract
Abstract MicroRNAs effectively modulate protein expression and cellular response. Unfortunately, the lack of robust nonviral delivery platforms has limited the therapeutic application of microRNAs. Additionally, there is a shortage of drug‐screening platforms that are directly translatable from in vitro to in vivo. Here, a fiber substrate that provides nonviral delivery of microRNAs for in vitro and in vivo microRNA screening is introduced. As a proof of concept, difficult‐to‐transfect primary neurons are targeted and the efficacy of this system is evaluated in a rat spinal cord injury model. With this platform, enhanced gene‐silencing is achieved in neurons as compared to conventional bolus delivery (p < 0.05). Thereafter, four well‐recognized microRNAs (miR‐21, miR‐222, miR‐132, and miR‐431) and their cocktails are screened systematically. Regardless of age and origin of the neurons, similar trends are observed. Next, this fiber substrate is translated into a 3D system for direct in vivo microRNA screening. Robust nerve ingrowth is observed as early as two weeks after scaffold implantation. Nerve regeneration in response to the microRNA cocktails is similar to in vitro experiments. Altogether, the potential of the fiber platform is demonstrated in providing effective microRNA screening and direct translation into in vivo applications.
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- 2019
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24. Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex‐specific pattern
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Tae Chung, Taylor Bopp, Chris Ward, Francesca M. Notarangelo, Robert Schwarcz, Reyhan Westbrook, Qian‐Li Xue, Jeremy Walston, and Ahmet Hoke
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Aging ,Cell Biology - Published
- 2023
25. MP27-12 FUNCTIONAL ERECTOGENIC NERVE MAPPING OF THE ENTIRE RAT PROSTATE WITH OPTICAL CLEARING
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Selman Unal, Biljana Musicki, Ahmet Hoke, and Arthur Burnett
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Urology - Published
- 2023
26. Grateful Giving in Medicine: A Personal Story
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Ahmet, Hoke
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General Medicine - Published
- 2022
27. Optimal outcome measures for assessing exercise and rehabilitation approaches in chemotherapy-induced peripheral-neurotoxicity: Systematic review and consensus expert opinion
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Susanna B. Park, Stefano Tamburin, Angelo Schenone, Ian R. Kleckner, Roser Velasco, Paola Alberti, Grace Kanzawa-Lee, Maryam Lustberg, Susan G. Dorsey, Elisa Mantovani, Mehrnaz Hamedani, Andreas A. Argyriou, Guido Cavaletti, Ahmet Hoke, Park, S, Tamburin, S, Schenone, A, Kleckner, I, Velasco, R, Alberti, P, Kanzawa-Lee, G, Lustberg, M, Dorsey, S, Mantovani, E, Hamedani, M, Argyriou, A, Cavaletti, G, and Hoke, A
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Consensus ,peripheral neuropathy ,exercise ,outcome measure ,treatment ,General Neuroscience ,Peripheral Nervous System Diseases ,Antineoplastic Agents ,Article ,rehabilitation ,cancer survivorship ,outcome measures ,Chemotherapy induced peripheral neurotoxicity ,neurotoxicity ,Neoplasms ,Outcome Assessment, Health Care ,Humans ,Pharmacology (medical) ,Neurology (clinical) ,Expert Testimony - Abstract
INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: The authors systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the significant gap in the identification of effective rehabilitation and treatment options for CIPN.
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- 2022
28. Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration after peripheral nerve injury
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Andrés Fuentes-Flores, Cristian Geronimo-Olvera, David Ñecuñir, Sandip Kumar Patel, Joanna Bons, Megan C. Wright, Daniel Geschwind, Ahmet Hoke, Jose A. Gomez-Sanchez, Birgit Schilling, Judith Campisi, and Felipe A. Court
- Abstract
After peripheral nerve injuries, successful axonal growth and functional recovery requires the reprogramming of Schwann cells into a reparative phenotype, a process dependent on the activation of the transcription factor c-Jun. Nevertheless, axonal regeneration is greatly impaired in aged organisms or after chronic denervation leading to important clinical problems. This regenerative failure has been associated to a diminished c-Jun expression by Schwann cells, but whether the inability of these cells to maintain a repair state is associated to the transition into a phenotype inhibitory for axonal growth, has not been evaluated so far. We find that repair Schwann cells transitions into a senescent phenotype, characterized by diminished c-Jun expression and secretion of factor inhibitory for axonal regeneration in both aging and chronic denervation. In both conditions, elimination of senescent Schwann cells by systemic senolytic drug treatment or genetic targeting improves nerve regeneration and functional recovery in aging and chronic denervation, associated with an upregulation of c-Jun expression and a decrease in nerve inflammation. This work provides the first characterization of senescent Schwann cells and their impact over axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration, and functional recovery after peripheral nerve injuries.
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- 2022
29. Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy
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Michael Polydefkis, Ahmet Hoke, Justin C. McArthur, Monica M. Diaz, Michelli F. Oliveira, Ken Perry, Ricardo H. Roda, David B. Clifford, Leah H. Rubin, Weiran Chen, Ajay R. Bharti, David Bargiela, Christina Gavegnano, Asha R. Kallianpur, and Ronald J. Ellis
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Male ,0301 basic medicine ,HIV Infections ,Neurodegenerative ,Gastroenterology ,0302 clinical medicine ,Skin ,medicine.diagnostic_test ,Pain Research ,Peripheral Nervous System Diseases ,Middle Aged ,Mitochondrial ,Infectious Diseases ,medicine.anatomical_structure ,Cohort ,HIV/AIDS ,Cognitive Sciences ,Female ,Chronic Pain ,Viral load ,Research Article ,Adult ,Mitochondrial DNA ,medicine.medical_specialty ,Clinical Sciences ,Nerve fiber ,Sural nerve ,DNA, Mitochondrial ,03 medical and health sciences ,Sural Nerve ,Clinical Research ,Internal medicine ,Genetics ,medicine ,Humans ,Peroneal Neuropathies ,Peripheral Neuropathy ,Retrospective Studies ,Neurology & Neurosurgery ,business.industry ,Neurosciences ,Retrospective cohort study ,DNA ,Clinical trial ,030104 developmental biology ,Mutation ,Skin biopsy ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveThe primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures.MethodsIn this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures.ResultsSixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32–65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3(SD 97 cells/mm3, range 1–416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147–657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r= −0.344,p= 0.04) and sural nerve amplitude (r= −0.359,p= 0.004).ConclusionsBoth IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.
- Published
- 2021
30. Ethoxyquin is neuroprotective and partially prevents somatic and autonomic neuropathy in db/db mouse model of type 2 diabetes
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Michael Polydefkis, Jing Zhu, Yuan Sun, Ahmet Hoke, Ruifa Mi, Osefame Ewaleifoh, Josh Wei, and Ying Liu
- Subjects
medicine.medical_specialty ,Diabetic neuropathy ,Myelin biology and repair ,Science ,Neural Conduction ,030209 endocrinology & metabolism ,Hindlimb ,Neuroprotection ,DNA, Mitochondrial ,Article ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ethoxyquin ,Diabetic Neuropathies ,Internal medicine ,medicine ,Animals ,Autonomic nervous system ,Multidisciplinary ,business.industry ,medicine.disease ,Sciatic Nerve ,Db/db Mouse ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Peripheral neuropathy ,Neuroprotective Agents ,chemistry ,Diabetes Mellitus, Type 2 ,Peripheral nervous system ,Mutation ,Diseases of the nervous system ,Medicine ,Sciatic nerve ,business ,Somatic system ,030217 neurology & neurosurgery - Abstract
Ethoxyquin (EQ), a quinolone-based antioxidant, has demonstrated neuroprotective properties against several neurotoxic drugs in a phenotypic screening and is shown to protect axons in animal models of chemotherapy-induced peripheral neuropathy. We assessed the effects of EQ on peripheral nerve function in the db/db mouse model of type II diabetes. After a 7 week treatment period, 12-week-old db/db-vehicle, db/+ -vehicle and db/db-EQ treated animals were evaluated by nerve conduction, paw withdrawal against a hotplate, and fiber density in hindlimb footpads. We found that the EQ group had shorter paw withdrawal latency compared to vehicle db/db group. The EQ group scored higher in nerve conduction studies, compared to vehicle-treated db/db group. Morphology studies yielded similar results. To investigate the potential role of mitochondrial DNA (mtDNA) deletions in the observed effects of EQ, we measured total mtDNA deletion burden in the distal sciatic nerve. We observed an increase in total mtDNA deletion burden in vehicle-treated db/db mice compared to db/+ mice that was partially prevented in db/db-EQ treated animals. These results suggest that EQ treatment may exert a neuroprotective effect in diabetic neuropathy. The prevention of diabetes-induced mtDNA deletions may be a potential mechanism of the neuroprotective effects of EQ in diabetic neuropathy.
- Published
- 2021
31. In Memoriam: Daniel B. Drachman
- Author
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Justin C. McArthur, Klaus Toyka, and Ahmet Hoke
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Neurology ,Neurology (clinical) - Published
- 2022
32. Deficiency of adaptive immunity does not interfere with Wallerian degeneration.
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Christopher R Cashman and Ahmet Hoke
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Medicine ,Science - Abstract
Following injury, distal axons undergo the process of Wallerian degeneration, and then cell debris is cleared to create a permissive environment for axon regeneration. The innate and adaptive immune systems are believed to be critical for facilitating the clearance of myelin and axonal debris during this process. However, immunodeficient animal models are regularly used in transplantation studies investigating cell therapies to modulate the degenerative/regenerative response. Given the importance of the immune system in preparing a permissive environment for regeneration by clearing debris, animals lacking, in part or in full, a functional immune system may have an impaired ability to regenerate due to poor myelin clearance, and may, thus, be poor hosts to study modulators of regeneration and degeneration. To study this hypothesis, three different mouse models with impaired adaptive immunity were compared to wild type animals in their ability to degenerate axons and clear myelin debris one week following sciatic nerve transection. Immunofluorescent staining for axons and quantitation of axon density with nerve histomorphometry of the distal stump showed no consistent discrepancy between immunodeficient and wild type animals, suggesting axons tended to degenerate equally between the two groups. Debris clearance was assessed by macrophage density and relative myelin basic protein expression within the denervated nerve stump, and no consistent impairment of debris clearance was found. These data suggested deficiency of the adaptive immune system does not have a substantial effect on axon degeneration one week following axonal injury.
- Published
- 2017
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33. Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
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Elizabeth M. MacDonald, Eva Andres-Mateos, Rebeca Mejias, Jessica L. Simmers, Ruifa Mi, Jae-Sung Park, Stephanie Ying, Ahmet Hoke, Se-Jin Lee, and Ronald D. Cohn
- Subjects
Skeletal muscle ,Muscle atrophy pathophysiology ,TGF-β signaling ,Myostatin ,Denervation atrophy ,Medicine ,Pathology ,RB1-214 - Abstract
The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.
- Published
- 2014
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34. Abstract QS46: Schwann Cell-like Cells (iMDSC) Differentiated from Muscle-Derived Stem Cells (MDSC) Improve Neuromuscular Re-innervation and Functional Outcomes After Rodent Upper Extremity Peripheral Nerve Trauma
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Joseph Lopez, MD, Helen Xun, BS, Pooja Yesantharao, BS, MS, Leila Musavi, BS, Kim X. Sinan, BS, Howard D. Wang, MD, Amy Quan, MD, Markus Tammia, Ph.D, Aysel Cetinkaya-Fisgin, Ph.D, Ahmet Hoke, MD Ph.D, Gerald Brendacher, MD, WP, Andrew Lee, MD, and Anand Kumar, MD
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Surgery ,RD1-811 - Published
- 2018
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35. Abstract 107: IGF-1 Nanoparticles Improve Functional Recovery After Nerve Repair
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Philip Hanwright, MD, Chenhu Qiu, BS, Jennifer Rath, BS, Nicholas von Guionneau, MBBS, Karim Sarhane, MD, Thomas Harris, Harsha Malapati, BS, W. P. Andrew Lee, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, and Sami Tuffaha, MD
- Subjects
Surgery ,RD1-811 - Published
- 2019
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36. Abstract 129: Molecular and Genetic Characterization of Functional Schwann-Cell Like Cells (iMDSCs) Transformed from Muscle Derived Stem Cells
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Pooja S. Yesantharao, MS, Helen Xun, BS, Leila Musavi, BS, Howard Wang, MD, Amy Quan, MD, Markus Tammia, PhD, Aysel Cetinkaya-Fisgin, PhD, Ahmet Hoke, MD, PhD, Gerald Brandacher, MD, W P Andrew Lee, MD, and Joseph Lopez, MD
- Subjects
Surgery ,RD1-811 - Published
- 2019
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37. Idiopathic distal sensory polyneuropathy ACTTION diagnostic criteria
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Roi Treister, Giuseppe Lauria, Anne Louise Oaklander, Heikki Mansikka, Christopher H. Gibbons, Amanda C. Peltier, Elissa Ritt, Noah Kolb, Eva L. Feldman, James W. Russell, Josh Bell, Robert H. Dworkin, Todd Levine, Ahmet Hoke, A. Gordon Smith, Roy Freeman, Rayaz A. Malik, David N. Herrmann, Deborah Steiner, Nurcan Üçeyler, J. Robinson Singleton, Catharina G. Faber, Stephen Sainati, Michael Polydefkis, Simon Haroutounian, and Jennifer S. Gewandter
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Small Fiber Neuropathy ,Sensory polyneuropathy ,Sensory system ,Nerve fiber ,Nerve Fibers, Myelinated ,Food and drug administration ,Polyneuropathies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Nerve Fibers, Unmyelinated ,Views & Reviews ,business.industry ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Practice Guidelines as Topic ,Etiology ,Sensory neuropathy ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Sensory nerve - Abstract
ObjectiveTo present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research.MethodsThe Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria.ResultsAn iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs.ConclusionAdoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.
- Published
- 2020
38. Full Collection of Personal Narratives
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Reshma Jagsi, Joel S. Perlmutter, Brendan D. Curti, Leslie Matthews, Leah Murray, Ahmet Hoke, Lauren Draper, Michelle A. Burack, James Malone, Jon A. Kobashigawa, Brent R. Carr, Kenneth R. Adler, Cheryl J. Hadaway, and Kevin E. Behrns
- Subjects
General Medicine - Published
- 2022
39. A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems.
- Author
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J Samuel Zigler, Colin A Hodgkinson, Megan Wright, Andrew Klise, Olof Sundin, Karl W Broman, Fielding Hejtmancik, Hao Huang, Bonnie Patek, Yuri Sergeev, Stacey Hose, Cory Brayton, Jiao Xaiodong, David Vasquez, Nicholas Maragakis, Susumu Mori, David Goldman, Ahmet Hoke, and Debasish Sinha
- Subjects
Medicine ,Science - Abstract
A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.
- Published
- 2016
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40. cADPR induced calcium influx mediates axonal degeneration caused by paclitaxel
- Author
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Ahmet Hoke
- Subjects
Armadillo Domain Proteins ,Cyclic ADP-Ribose ,Cytoskeletal Proteins ,Paclitaxel ,Calcium ,Cell Biology ,Axons - Abstract
Activation of the NAD hydrolase domain of Sarm1 mediates axonal degeneration caused by chemotherapy drugs, but the downstream events are unknown. In this issue, Li and colleagues (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202106080) demonstrate that cADPR, a breakdown product of NAD, mediates paclitaxel-induced axonal degeneration by promoting influx of calcium into the axons.
- Published
- 2022
41. Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: systematic review and evidence-based recommendations
- Author
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Stefano Tamburin, Susanna B. Park, Angelo Schenone, Elisa Mantovani, Mehrnaz Hamedani, Paola Alberti, Vesile Yildiz-Kabak, Ian R. Kleckner, Noah Kolb, Miryam Mazzucchelli, Brendan L. McNeish, Andreas A. Argyriou, Guido Cavaletti, Ahmet Hoke, Tamburin, S, Park, S, Schenone, A, Mantovani, E, Hamedani, M, Alberti, P, Yildiz-Kabak, V, Kleckner, I, Kolb, N, Mazzucchelli, M, Mcneish, B, Argyriou, A, Cavaletti, G, and Hoke, A
- Subjects
Oncology ,exercise ,treatment ,Neoplasms ,Chemotherapy-induced peripheral neurotoxicity (CIPN) ,Evidence-based medicine ,Exercise ,Physical therapy ,Rehabilitation ,Treatment ,Humans ,Antineoplastic Agents ,Peripheral Nervous System Diseases ,physical therapy ,Hematology ,evidence-based medicine ,rehabilitation - Abstract
Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.
- Published
- 2022
42. Change of guard at <scp>ACTN</scp>
- Author
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Ahmet Hoke
- Subjects
General Neuroscience ,Neurology (clinical) - Published
- 2023
43. Normal structure and pathological features in peripheral neuropathies
- Author
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Angelo Quattrini, Ahmet Hoke, Federica Cerri, Aysel Fisgin, and Nilo Riva
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,General Neuroscience ,Peripheral Nervous System Diseases ,Axons ,Peripheral ,Myelin ,medicine.anatomical_structure ,nervous system ,Interstitial space ,medicine ,Humans ,Peripheral Nerves ,Neurology (clinical) ,Peripheral Nerve Disorders ,Axon ,Remyelination ,Differential diagnosis ,business ,Pathological ,Myelin Sheath - Abstract
Normal nerve architecture is basic to a complete understanding of nerve pathology. Here, normal components of the nerve are illustrated, including myelinated and non-myelinated nerve fibres, stromal elements, and vascular components. These are relevant because the differential diagnosis of neuropathy depends on the pathological processes affecting axon, myelin, interstitial space, and blood vessels. Thus, we present a description of the general pathological characteristics for the diagnosis of peripheral nerve disorders.
- Published
- 2021
44. Peripheral hyperstimulation alters site of disease onset and course in SOD1 rats
- Author
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Angelo C. Lepore, Christopher Tolmie, John O'Donnell, Megan C. Wright, Christine Dejea, Britta Rauck, Ahmet Hoke, Anthony R. Ignagni, Raymond P. Onders, and Nicholas J. Maragakis
- Subjects
Motor neuron ,Neurodegeneration ,ALS ,Amyotrophic lateral sclerosis ,SOD1 ,Phrenic nerve ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
In amyotrophic lateral sclerosis (ALS), the exogenous temporal triggers that result in initial motor neuron death are not understood. Overactivation and consequent accelerated loss of vulnerable motor neurons is one theory of disease initiation. The vulnerability of motor neurons in response to chronic peripheral nerve hyperstimulation was tested in the SOD1G93A rat model of ALS. A novel in vivo technique for peripheral phrenic nerve stimulation was developed via intra-diaphragm muscle electrode implantation at the phrenic motor endpoint. Chronic bilateral phrenic nerve hyperstimulation in SOD1G93A rats accelerated disease progression, including shortened lifespan, hastened motor neuron loss and increased denervation at diaphragm neuromuscular junctions. Hyperstimulation also resulted in focal decline in adjacent forelimb function. These results show that peripheral phrenic nerve hyperstimulation accelerates cell death of vulnerable spinal motor neurons, modifies both temporal and anatomical onset of disease, and leads to involvement of disease in adjacent anatomical regions in this ALS model.
- Published
- 2010
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45. Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair
- Author
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Nicholas von Guionneau, Sami H. Tuffaha, Hai-Quan Mao, Michael J. Lan, Gregory P. Howard, Sashank Reddy, Karim A. Sarhane, Thomas G.W. Harris, Jennifer Rath, Chenhu Qiu, Harsha Malapati, Philip J. Hanwright, Yang Zhou, and Ahmet Hoke
- Subjects
Senescence ,medicine.medical_treatment ,Biophysics ,Bioengineering ,Pharmacology ,Biomaterials ,Peripheral Nerve Injuries ,medicine ,Myocyte ,Animals ,Insulin-Like Growth Factor I ,Muscle, Skeletal ,Chemistry ,Regeneration (biology) ,Growth factor ,Recovery of Function ,Controlled release ,Denervation ,Muscle atrophy ,Nerve Regeneration ,Rats ,medicine.anatomical_structure ,Mechanics of Materials ,Peripheral nerve injury ,Ceramics and Composites ,Schwann Cells ,medicine.symptom ,Reinnervation - Abstract
Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.
- Published
- 2021
46. Immortalized Human Schwann Cell Lines Derived From Tumors of Schwannomatosis Patients.
- Author
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Kimberly Laskie Ostrow, Katelyn Donaldson, Jaishri Blakeley, Allan Belzberg, and Ahmet Hoke
- Subjects
Medicine ,Science - Abstract
Schwannomatosis, a rare form of neurofibromatosis, is characterized predominantly by multiple, often painful, schwannomas throughout the peripheral nervous system. The current standard of care for schwannomatosis is surgical resection. A major obstacle to schwannomatosis research is the lack of robust tumor cell lines. There is a great need for mechanistic and drug discovery studies of schwannomatosis, yet appropriate tools are not currently available. Schwannomatosis tumors are difficult to grow in culture as they survive only a few passages before senescence. Our lab has extensive experience in establishing primary and immortalized human Schwann cell cultures from normal tissue that retain their phenotypes after immortalization. Therefore we took on the challenge of creating immortalized human Schwann cell lines derived from tumors from schwannomatosis patients. We have established and fully characterized 2 schwannomatosis cell lines from 2 separate patients using SV40 virus large T antigen. One patient reported pain and the other did not. The schwannomatosis cell lines were stained with S100B antibodies to confirm Schwann cell identity. The schwannomatosis cells also expressed the Schwann cell markers, p75NTR, S100B, and NGF after multiple passages. Cell morphology was retained following multiple passaging and freeze/ thaw cycles. Gene expression microarray analysis was used to compare the cell lines with their respective parent tumors. No differences in key genes were detected, with the exception that several cell cycle regulators were upregulated in the schwannomatosis cell lines when compared to their parent tumors. This upregulation was apparently a product of cell culturing, as the schwannomatosis cells exhibited the same expression pattern of cell cycle regulatory genes as normal primary human Schwann cells. Cell growth was also similar between normal primary and immortalized tumor cells in culture. Accurate cell lines derived directly from human tumors will serve as invaluable tools for advancing schwannomatosis research, including drug screening.
- Published
- 2015
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47. QS1: Pre-implanted Nerve Grafts (PING) to Improve Functional Outcomes in VCA
- Author
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Jamie T. Shores, Xiuyun Liu, Nicholas von Guionneau, Ahmet Hoke, Benjamin R. Slavin, Gerald Brandacher, Ruchita Kothari, Kimberly Khoo, Sami H. Tuffaha, Emily Finkelstein, Connor Glass, Joshua Yoon, Raymond Kohler, and Erica Lee
- Subjects
Ping (video games) ,medicine.medical_specialty ,RD1-811 ,business.industry ,medicine.medical_treatment ,Transplant recipient ,Nerve graft ,Functional recovery ,Vascularized Composite Allotransplantation ,Surgery ,body regions ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Amputation ,PSRC 2021 Abstract Supplement ,medicine ,business ,Reinnervation - Abstract
Purpose: Improved graft reinnervation and functional recovery would greatly enhance the utility of vascularized composite allotransplantation (VCA). Pre-implantation of nerve grafts in a limb transplant recipient prior to transplantation to increase the length of the severed nerves in the amputation stump offers a novel, readily translatable approach to this problem. At the time of transplantation a pre-implanted nerve graft (PING) would be elevated from its wound bed in the amputated stump and unfurled distally into the transplanted limb, allowing for a more distal nerve coaptation. Methods: We used a reversed sciatic-tibial nerve isograft coapted end-to-end to a median nerve in a rat to: (1) determine viability of distal axons after elevating PINGs; and (2) assess for ischemic injury to axons in the distal PING following elevation from the wound bed. For axonal viability, grafts of varying lengths (2cm,3cm,4cm, n≥5/group) were left to regenerate for 8 weeks. The distal ends were then biopsied prior to elevation, and again one week after elevation. For ischemia assessment, blood flow along 4cm long PINGs was measured with laser doppler at multiple timepoints: baseline (at time of grafting), 8 weeks after grafting (before elevation), immediately after elevation, and 3 and 7 days post-elevation (n=8/timepoint). Means were compared with t-tests and ANOVA. A pig forelimb model was used to assess the functional impact of PINGs. A 6cm long reversed ulnar-PING was coapted to the proximally transected ulnar nerve. After 12 weeks of regeneration, the distal PING was transferred end-to-end to the median nerve just proximal to the elbow. A control group underwent ulnar-to-median nerve transfer 6cm proximal to the elbow (n=4 limbs/group). Hoof flexion force was measured every three weeks. Results Axonal viability: after 8 weeks, axons had regenerated into the distal grafts in all lengths: mean myelinated axon counts (±SD): 7043 (±790), 6066 (±1838), 6491 (±983) in 2cm,3cm,4cm grafts, with no differences between graft lengths (p=0.48). One week after elevation and unfurling, the number of myelinated axons was significantly decreased in all groups (p
- Published
- 2021
48. Development of EQ-6, a Novel Analogue of Ethoxyquin to Prevent Chemotherapy-Induced Peripheral Neuropathy
- Author
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Rana Rais, Jing Zhu, Cory Brayton, Jun Soon Kim, Byoungchol Oh, Jesse Alt, Aysel Cetinkaya-Fisgin, Xinghua Luan, Ahmet Hoke, and Barbara S. Slusher
- Subjects
Male ,Side effect ,Antineoplastic Agents ,Pharmacology ,Neuroprotection ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Ethoxyquin ,Dorsal root ganglion ,Drug Development ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Axon ,Cells, Cultured ,business.industry ,Peripheral Nervous System Diseases ,medicine.disease ,Rats ,Peripheral neuropathy ,medicine.anatomical_structure ,chemistry ,Chemotherapy-induced peripheral neuropathy ,Mechanism of action ,Original Article ,Female ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and often dose-limiting side effect of many cancer drugs. Because the onset of neuronal injury is known, it is an ideal clinical target to develop neuroprotective strategies. Several years ago, we had identified ethoxyquin as a potent neuroprotective drug against CIPN through a phenotypic drug screening and demonstrated a novel mechanism of action, inhibition of chaperone domain of heat shock protein 90. To improve its drug-like properties we synthesized a novel analogue of ethoxyquin and named it EQ-6 (6-(5-amino)-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride). Here we show that EQ-6 prevents axon degeneration in primary dorsal root ganglion neurons in vitro, and this axon protection is associated with preserved levels of nicotinamide adenine dinucleotide, a key metabolite in programmed axon degeneration pathway. We also found that EQ-6 prevents loss of epidermal nerve fibers in a mouse model of CIPN induced by paclitaxel and that doses of EQ-6 that provide neuroprotection are associated with reduced tissue levels of SF3B2, a potential biomarker of target engagement. Furthermore, we show that EQ-6 is safe in vitro and in mice with daily administration for a month. We found that oral bioavailability is about 10%, partly due to rapid metabolism in liver, but EQ-6 appears to be concentrated in neural tissues. Given these findings, we propose EQ-6 as a first-in-class drug to prevent CIPN. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01093-8.
- Published
- 2021
49. Novel genetic form of amyotrophic lateral sclerosis reveals metabolic mechanism and therapeutic target
- Author
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Florian P. Thomas, Carsten G. Bönnemann, Zoe Piccus, Aliza Zidell, Ana Lucila Moreira, Matthew Nalls, S. Neuhaus, Mark A. Tarnopolsky, Helio Pedro, Fernando Kok, Eric Mittelmann, Kenneth Gable, Lauren Brady, Chamindra G. Konersman, Teresa M. Dunn, Anne M. Connolly, Alessandro Introna, Katherine R. Chao, Robert H. Brown, Tracy Brandt, Sabine Specht, Thorsten Hornemann, Museer A. Lone, Alec R. Nickolls, Volker Straub, Andreas Roos, Ahmet Hoke, Giancarlo Logroscino, Chiara Fiorillo, Claire E. Le Pichon, Chia-Hsueh Lee, Cindy V. Ly, A. Reghan Foley, Dimah Saade, Megan T. Cho, Sita D. Gupta, Ying Hu, Payam Mohassel, Andrea Gangfuß, Heike Kölbel, Christopher Grunseich, Jonas Alex Morales Saute, Sandra Donkervoort, Ana Töpf, Ulrike Schara, and Naemeh Pourshafie
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Alleles ,Amino Acid Sequence ,Amyotrophic Lateral Sclerosis ,CRISPR-Cas Systems ,Child ,Female ,Genes, Dominant ,HEK293 Cells ,Humans ,Middle Aged ,Mutation ,Serine C-Palmitoyltransferase ,Sphingolipids ,Young Adult ,Medizin ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Serine ,Cellular and Molecular Neuroscience ,03 medical and health sciences ,Text mining ,0302 clinical medicine ,Hereditary sensory and autonomic neuropathy ,medicine ,Dominant ,SPTLC1 ,Allele ,Amyotrophic lateral sclerosis ,Genetics ,business.industry ,Mechanism (biology) ,Serine C-palmitoyltransferase ,General Medicine ,Motor neuron ,medicine.disease ,Sphingolipid ,030104 developmental biology ,medicine.anatomical_structure ,Genes ,030220 oncology & carcinogenesis ,Neurology (clinical) ,business ,Neuroscience - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
- Published
- 2021
50. The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity
- Author
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Allan J. Belzberg, Katelyn J. Donaldson, Ahmet Hoke, Kimberly Laskie Ostrow, and Michael J. Caterina
- Subjects
Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Neurofibromatoses ,Sensory Receptor Cells ,TRPV1 ,lcsh:Medicine ,Chronic pain ,Molecular neuroscience ,Article ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,Ganglia, Spinal ,Medicine ,Animals ,Humans ,Schwannomatosis ,lcsh:Science ,TRPA1 Cation Channel ,Sensitization ,Regulation of gene expression ,Multidisciplinary ,business.industry ,lcsh:R ,Depolarization ,Cancer Pain ,medicine.disease ,Sensory neuron ,Peripheral ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Nociception ,lcsh:Q ,business ,Neurilemmoma - Abstract
Schwannomatosis is a multiple tumor syndrome in which patients develop benign tumors along peripheral nerves throughout the body. The first symptom with which schwannomatosis patients often present, prior to discovery of tumors, is pain. This pain can be debilitating and is often inadequately alleviated by pharmacological approaches. Schwannomatosis-associated pain can be localized to the area of a tumor, or widespread. Moreover, not all tumors are painful, and the occurrence of pain is often unrelated to tumor size or location. We speculate that some individual tumors, but not others, secrete factors that act on nearby nerves to augment nociception by producing neuronal sensitization or spontaneous neuronal firing. We created cell lines from human SWN tumors with varying degrees of pain. We have found that conditioned medium (CM) collected from painful SWN tumors, but not that from nonpainful SWN tumors, sensitized DRG neurons, causing increased sensitivity to depolarization by KCl, increased response to noxious TRPV1 and TRPA1 agonists and also upregulated the expression of pain-associated genes in DRG cultures. Multiple cytokines were also detected at higher levels in CM from painful tumors. Taken together our data demonstrate a differential ability of painful versus non-painful human schwannomatosis tumor cells to secrete factors that augment sensory neuron responsiveness, and thus identify a potential determinant of pain heterogeneity in schwannomatosis.
- Published
- 2019
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