2,149 results on '"Machado–Joseph disease"'
Search Results
2. Instrumented Data Exchange for Ataxia Study (IDEA)
- Author
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Pfizer, Biogen, and APDM Wearable Technologies
- Published
- 2024
3. Priming Motor Learning Through Exercise in People With Spinocerebellar Ataxia (PRIME-Ataxia)
- Published
- 2024
4. STRIDES - a Clinical Research Study of an Investigational New Drug to Treat Spinocerebellar Ataxia (STRIDES)
- Published
- 2024
5. Umbilical Cord Mesenchymal Stem Cells Therapy (19#iSCLife®-SA) for Patients With Spinocerebellar Ataxia
- Published
- 2024
6. A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD
- Published
- 2024
7. Troriluzole in Adult Subjects With Spinocerebellar Ataxia
- Published
- 2024
8. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford (CoRDS)
- Author
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National Ataxia Foundation, International WAGR Syndrome Association, 4p- Support Group, ML4 Foundation, Cornelia de Lange Syndrome Foundation, Stickler Involved People, Kawasaki Disease Foundation, Klippel-Feil Syndrome Alliance, Klippel-Feil Syndrome Freedom, Hyperacusis Research Limited, Hypersomnia Foundation, Kabuki Syndrome Network, Kleine-Levin Syndrome Foundation, Leiomyosarcoma Direct Research Foundation, Marinesco-Sjogren Syndrome Support Group - NORD, Mucolipidosis Type IV (ML4) Foundation, People with Narcolepsy 4 People with Narcolepsy (PWN4PWN), Soft Bones Incorporated, American Multiple Endocrine Neoplasia Support, Atypical Hemolytic Uremic Syndrome Foundation, All Things Kabuki, Wiedemann-Steiner Syndrome Foundation, Breast Implant Victim Advocates, PROS Foundation, American Behcet's Disease Association, Alstrom United Kingdom, Athymia, Curing Retinal Blindness Foundation, HSAN1E Society, 1p36 Deletion Support and Awareness, The Alagille Syndrome Alliance, Autoinflammatory Alliance, Beyond Batten Disease Foundation, Bohring-Opitz Syndrome Foundation, INC, Cockayne Syndrome Network (Share and Care), CRMO Foundation, Cure VCP Disease,INC, FOD Support, Cystinosis Research Foundation, Global DARE Foundation, Hypnic Jerk-Sleep Myoclonus Support Group, Jansen's Foundation, KCNMA1 Channelopathy International Advocacy Foundation, Kawasaki Disease Foundation Australia, Life with LEMS Foundation, Lowe Syndrome Association, The Malan Syndrome Foundation, Maple Syrup Urine Disease Family Support Group, International Association for Muscle Glycogen Storage Disease (IamGSD), Myhre Syndrome Foundation, DNM1 Families, Nicolaides Baraitser Syndrome (NCBRS) Worldwide Foundation, The PBCers Organization, Pitt Hopkins Research Foundation, Recurrent Meningitis Association, Recurrent Respiratory Papillomatosis Foundation, Remember the Girls, Smith-Kingsmore Syndrome Foundation, SPG Research Foundation, Team Telomere, Transient Global Amnesia Project, The Charlotte & Gwenyth Gray Foundation, The Cute Syndrome Foundation, The Maddi Foundation, White Sutton Syndrome Foundation, Zmynd11 Gene Disorder, Cauda Equina Foundation, Inc, Tango2 Research Foundation, Noah's Hope - Hope4Bridget Foundation, Project Sebastian, SMC1A Epilepsy Foundation, International Foundation for Gastrointestinal Disorders, Endosalpingiosis Foundation, Inc, International Sacral Agenesis/Caudal Regression Association (ISACRA), Scheuermann's Disease Fund, Batten Disease Support and Research Association, Kennedy's Disease Association, Cure Mito Foundation, Warburg Micro Research Foundation, Cure Mucolipidosis, Riaan Research Initiative, CureARS A NJ Nonprofit Corporation, CACNA1H Alliance, IMBS Alliance, SHINE-Syndrome Foundaion, Non- Ketotic Hyperglycinemia (NKH) Crusaders, Hypertrophic Olivary Degeneration Association (HODA), National Organization for Disorders of the Corpus Callosum (NODCC), Team4Travis, Taylor's Tale Foundation, Lambert Eaton (LEMS) Family Association, BARE Inc, STAG1 Gene Foundation, Coffin Lowry Syndrome Foundation, BLFS Incorporate, Aniridia North America, Cure Blau Syndrome Foundation, ARG1D Foundation, CURE HSPB8 Myopathy, International Society of Mannosidosis and Related Disorders, TBX4Life, Cure DHDDS, MANDKind Foundation, Krishnan Family Foundation, and SPATA Foundation
- Published
- 2024
9. Aboriginal families living with MJD in remote Australia: questions of access and equity.
- Author
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Massey, Libby, Gilroy, John, Kowal, Emma, Doolan, Denise, and Clough, Alan
- Subjects
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HEALTH services accessibility , *GENOMICS , *MEDICAL technology , *CEREBELLUM diseases , *HEALTH , *INFORMATION resources , *RURAL conditions , *X-linked genetic disorders , *HEALTH equity , *HEALTH care rationing - Abstract
Managing genetic disease using medically assisted reproductive technology is increasingly promoted as a feasible option, given revolutionary advances in genomics. Far less attention has been directed to the issue of whether there is equitable access to this option. Context and circumstance determine equitable access; however, reporting has drawn overwhelmingly from affluent Anglo-western populations in developed countries. The experiences of poorer, less educated subpopulations within affluent countries and populations in less developed countries are underreported. The ability of consumers to understand the opportunities and risks of medically assisted reproductive technology is likewise not well described in the literature despite significant technological complexity and evidence that genetic disease may be overrepresented within some disadvantaged population groups. Equity is achieved by identifying barriers and allocating appropriate resources to enable understanding and access. In the case of utilising medically assisted technology, social and power relationships, regulations, and the presumptions of authority figures and policymakers reduce equitable access. Physical or cultural marginalisation from mainstream health services may result in reduced access to genetic and prenatal testing, in-vitro fertilisation and genetic screening of embryos necessary for medically assisted reproduction. Cost and regulatory frameworks can likewise limit opportunities to engage with services. Moreover, the quality of the information provided to prospective users of the technology and how it is received governs understanding of prevention and inhibits adequately informed choice. Best practice care and adequately informed choice can only be achieved by conscientiously attending to these accessibility issues. Deep engagement with at-risk people and critical reflection on mainstream accepted standpoints is required. This paper outlines issues associated with engaging with medically assisted reproduction encountered by Aboriginal families living with Machado-Joseph Disease in some of the most remote areas of Australia. It is the right of these families to access such technologies regardless of where they live. Current barriers to access raise important questions for service providers with implications for practice as new technologies increasingly become part of standard medical care. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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10. Progression of Retinal Ganglion Cell and Nerve Fiber Layer Loss in Spinocerebellar Ataxia 3 Patients.
- Author
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Camós-Carreras, Anna, Figueras-Roca, Marc, Dotti-Boada, Marina, Alcubierre, Rafel, Casaroli-Marano, Ricardo Pedro, Muñoz, Esteban, and Sánchez-Dalmau, Bernardo
- Subjects
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RETINAL ganglion cells , *SPINOCEREBELLAR ataxia , *NEURONS , *OPTICAL coherence tomography , *NERVE fibers , *DISEASE duration - Abstract
Spectral domain optical coherence tomography (SD-OCT) allows noninvasive measurements of retinal neuron layers. Here, we evaluate the relationship between clinical features and anatomical SD-OCT measurements in patients with spinocerebellar ataxia type 3 (SCA3) and how they change with time. A retrospective review was conducted on SCA3 patients. Clinical variables such as disease duration, number of CAG repeats, and the Scale for the Assessment and Rating of Ataxia (SARA) score were correlated with SD-OCT measurements, including retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, macular volume (MV), and central macular thickness (CMT). Seventeen SCA3 patients with an average follow-up of 44.9 months were recruited. Clinical features with significant baseline correlations with SD-OCT measurements included disease duration (CMT r = − 0.590; GCC r = − 0.585), SARA score (CMT r = − 0.560; RNFL r = − 0.390), and number of CAG repeats (MV r = − 0.552; RNFL r = − 0.503; GCC r = − 0.493). The annual rate of change of the SARA score during follow-up was associated with that of both the MV (r = − 0.494; p = 0.005) and GCC thickness (r = − 0.454; p = 0.012). High disability (stages 2 and 3) was independently inversely associated with the annual change in MV (ß coefficient − 17.09; p = 0.025). This study provides evidence of an association between clinical features and objective anatomical measurements obtained by SD-OCT in SCA3 patients. MV and GCC thickness could serve as potential biomarkers of disease severity, as their rates of decrease seem to be related to a worsening in the SARA score. These findings highlight the potential of SD-OCT as a noninvasive tool for assessing disease severity and progression in SCA3 patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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11. "I Do Not Know How You Feel and How I Feel About That": Mentalizing Impairments in Machado-Joseph Disease.
- Author
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Elyoseph, Zohar, Geisinger, Dario, Nave-Aival, Erez, Zaltzman, Roy, and Gordon, Carlos R.
- Subjects
- *
CEREBELLUM degeneration , *MENTALIZATION , *PATIENTS' attitudes , *SPINOCEREBELLAR ataxia , *TELEPATHY , *THEORY of mind - Abstract
Machado Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. Mentalizing is the ability to think and understand the mental state of the other and of the self in terms of thoughts, feelings, and intentions. The aim of this study is to fill the gap in our understanding of mentalizing in MJD since there is currently very little and inconsistent research on MJD and mentalizing. A total of 18 Jews of Yemenite origin with clinically and genetically confirmed MJD, 5 pre-symptomatic MJD with a positive genetic test, and 17 Jews of Yemenite origin healthy controls, underwent a battery of tests consisting of reading the mind in the eyes (RME), Toronto Alexithymia Scale (TAS-20), and false belief test (FBt). The MJD group scored lower on the RME and FBt, and higher on TAS-20 test compared to control. A significant negative correlation was found between disease duration and RME score. All the pre-symptomatic participants scored within the normal clinical range in all tests. MJD patients demonstrated a widespread deficiency in the ability to mentalizing on a clinical level with autistic characteristics. These impairments may impact the patient's interpsychic experience and daily life interactions and have important clinical implication. Pre-symptomatic participants demonstrated normal mentalizing in all tests, suggesting that the mentalizing impairments do not precede the symptoms of ataxia and are part of the clinical picture of MJD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. Specific Biomarkers in Spinocerebellar Ataxia Type 3: A Systematic Review of Their Potential Uses in Disease Staging and Treatment Assessment.
- Author
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Soto-Piña, Alexandra E., Pulido-Alvarado, Caroline C., Dulski, Jaroslaw, Wszolek, Zbigniew K., and Magaña, Jonathan J.
- Subjects
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SPINOCEREBELLAR ataxia , *BODY fluids , *THERAPEUTICS , *DISEASE progression , *OXIDATIVE stress - Abstract
Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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13. Production of Spinocerebellar Ataxia Type 3 Model Mice by Intravenous Injection of AAV-PHP.B Vectors.
- Author
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Konno, Ayumu, Shinohara, Yoichiro, and Hirai, Hirokazu
- Subjects
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SPINOCEREBELLAR ataxia , *INTRAVENOUS injections , *ANIMAL disease models , *CEREBELLAR nuclei , *LABORATORY mice , *FOOTPRINTS , *BLOOD-brain barrier - Abstract
We aimed to produce a mouse model of spinocerebellar ataxia type 3 (SCA3) using the mouse blood–brain barrier (BBB)-penetrating adeno-associated virus (AAV)-PHP.B. Four-to-five-week-old C57BL/6 mice received injections of high-dose (2.0 × 1011 vg/mouse) or low-dose (5.0 × 1010 vg/mouse) AAV-PHP.B encoding a SCA3 causative gene containing abnormally long 89 CAG repeats [ATXN3(Q89)] under the control of the ubiquitous chicken β-actin hybrid (CBh) promoter. Control mice received high doses of AAV-PHP.B encoding ATXN3 with non-pathogenic 15 CAG repeats [ATXN3(Q15)] or phosphate-buffered saline (PBS) alone. More than half of the mice injected with high doses of AAV-PHP.B encoding ATXN3(Q89) died within 4 weeks after the injection. No mice in other groups died during the 12-week observation period. Mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89) exhibited progressive motor uncoordination starting 4 weeks and a shorter stride in footprint analysis performed at 12 weeks post-AAV injection. Immunohistochemistry showed thinning of the molecular layer and the formation of nuclear inclusions in Purkinje cells from mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89). Moreover, ATXN3(Q89) expression significantly reduced the number of large projection neurons in the cerebellar nuclei to one third of that observed in mice expressing ATXN3(Q15). This AAV-based approach is superior to conventional methods in that the required number of model mice can be created simply by injecting AAV, and the expression levels of the responsible gene can be adjusted by changing the amount of AAV injected. Moreover, this method may be applied to produce SCA3 models in non-human primates. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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14. Identification of Biomarkers in Spinocerebellar Ataxia 3 (SCA3)
- Author
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National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), and Henry Paulson, Professor of Neurology
- Published
- 2023
15. Functional impact of bilateral vestibular loss and the unexplained complaint of oscillopsia.
- Author
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Geisinger, Dario, Elyoseph, Zohar, Zaltzman, Roy, Mintz, Matti, and Gordon, Carlos R.
- Subjects
VESTIBULAR apparatus diseases ,SPATIAL orientation ,VESTIBULO-ocular reflex ,EYE movements ,VISUAL acuity ,MEDICAL centers - Abstract
Introduction: The vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia. Methods: Participants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado-Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center. Results: Among the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test. Discussion: Even though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
16. Genetic Epidemiology and Clinical Characteristics of Patients with Spinocerebellar Ataxias in an Unexplored Brazilian State, Using Strategies for Resource-Limited Settings.
- Author
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Moraes, Débora Beserra Vilar, Coradine, Tácio Luis Cavalcante, Silva, Everton Vieira Lopes, Sobreira-Neto, Manoel Alves, Marques Jr, Wilson, Gitaí, Lívia Leite Góes, and Tumas, Vitor
- Subjects
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RESOURCE-limited settings , *GENETIC epidemiology , *CLINICAL epidemiology , *HUMAN Development Index , *GAIT disorders - Abstract
Spinocerebellar ataxias (SCAs) have a worldwide average prevalence of 2.7 cases per 100,000 individuals, with significant geographic variability. This study aimed to develop resource-limited strategies to detect and characterize the frequency and genetic-clinical profile of SCAs in an unexplored population from Alagoas State, a low Human Development Index state in northeastern Brazil. Active search strategies were employed to identify individuals with a diagnosis or clinical suspicion of SCAs, and a protocol for clinical and molecular evaluation was applied in collaboration with a reference center in Neurogenetics. A total of 73 individuals with SCAs were identified, with a minimum estimated prevalence of 2.17 cases per 100,000 inhabitants. SCA3 was the most common type (75.3%), followed by SCA7 (15.1%), SCA1 (6.8%), and SCA2 (2.7%). Patients with SCA3 subphenotype 2 were the most predominant. Detailed analysis of patients with SCA3 and SCA7 revealed age at onset and clinical features congruent with other studies, with gait disturbance and reduced visual capacity in SCA7 as the main initial manifestations. The study also identified many asymptomatic individuals at risk of developing SCAs. These findings demonstrate that simple and collaborative strategies can enhance the detection capacity of rare diseases such as SCAs in resource-limited settings and that Alagoas State has a minimum estimated prevalence of SCAs similar to the world average. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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17. Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3.
- Author
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Tezenas du Montcel, Sophie, Petit, Emilien, Olubajo, Titilayo, Faber, Jennifer, Lallemant-Dudek, Pauline, Bushara, Khalaf, Perlman, Susan, Subramony, Sub, Morgan, David, Jackman, Brianna, Paulson, Henry, Öz, Gülin, Klockgether, Thomas, Durr, Alexandra, and Ashizawa, Tetsuo
- Subjects
Humans ,Prospective Studies ,Spinocerebellar Ataxias ,Cerebellar Ataxia ,Cerebellum ,Biomarkers ,Machado-Joseph Disease - Abstract
BACKGROUND AND OBJECTIVES: In spinocerebellar ataxia, ataxia onset can be preceded by mild clinical manifestation, cerebellar and/or brainstem alterations, or biomarker modifications. READISCA is a prospective, longitudinal observational study of patients with spinocerebellar ataxia type 1 (SCA1) and 3 (SCA3) to provide essential markers for therapeutic interventions. We looked for clinical, imaging, or biological markers that are present at an early stage of the disease. METHODS: We enrolled carriers of a pathologic ATXN1 or ATXN3 expansion and controls from 18 US and 2 European ataxia referral centers. Clinical, cognitive, quantitative motor, neuropsychological measures and plasma neurofilament light chain (NfL) measurements were compared between expansion carriers with and without ataxia and controls. RESULTS: We enrolled 200 participants: 45 carriers of a pathologic ATXN1 expansion (31 patients with ataxia [median Scale for the Assessment and Rating of Ataxia: 9; 7-10] and 14 expansion carriers without ataxia [1; 0-2]) and 116 carriers of a pathologic ATXN3 expansion (80 patients with ataxia [7; 6-9] and 36 expansion carriers without ataxia [1; 0-2]). In addition, we enrolled 39 controls who did not carry a pathologic expansion in ATXN1 or ATXN3. Plasma NfL levels were significantly higher in expansion carriers without ataxia than controls, despite similar mean age (controls: 5.7 pg/mL, SCA1: 18.0 pg/mL [p < 0.0001], SCA3: 19.8 pg/mL [p < 0.0001]). Expansion carriers without ataxia differed from controls by significantly more upper motor signs (SCA1 p = 0.0003, SCA3 p = 0.003) and by the presence of sensor impairment and diplopia in SCA3 (p = 0.0448 and 0.0445, respectively). Functional scales, fatigue and depression scores, swallowing difficulties, and cognitive impairment were worse in expansion carriers with ataxia than those without ataxia. Ataxic SCA3 participants showed extrapyramidal signs, urinary dysfunction, and lower motor neuron signs significantly more often than expansion carriers without ataxia. DISCUSSION: READISCA showed the feasibility of harmonized data acquisition in a multinational network. NfL alterations, early sensory ataxia, and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and expansion carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03487367.
- Published
- 2023
18. A Pharmacokinetics and Safety Study of BIIB132 in Adults With Spinocerebellar Ataxia 3
- Published
- 2023
19. Spinocerebellar Ataxias: Phenotypic Spectrum of PolyQ versus Non-Repeat Expansion Forms
- Author
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Moura, João, Oliveira, Jorge, Santos, Mariana, Costa, Sara, Silva, Lénia, Lemos, Carolina, Barros, José, Sequeiros, Jorge, and Damásio, Joana
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- 2024
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20. Caffeine Consumption and Interaction with ADORA2A, CYP1A2 and NOS1 Variants Do Not Influence Age at Onset of Machado-Joseph Disease
- Author
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Martins, Ana Carolina, Pinheiro, Jordânia dos Santos, Szinwelski, Luciana, Cidade, Eduardo Rockenbach, Santin, Danilo Fernando, Proença, Laura Damke, Araújo, Bruna Almeida, Saraiva-Pereira, Maria Luiza, and Jardim, Laura Bannach
- Published
- 2024
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21. Spermidine treatment: induction of autophagy but also apoptosis?
- Author
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Maxinne Watchon, Amanda L. Wright, Holly I. Ahel, Katherine J. Robinson, Stuart K. Plenderleith, Andrea Kuriakose, Kristy C. Yuan, and Angela S. Laird
- Subjects
Machado-Joseph disease ,Neurodegeneration ,PolyQ ,Spinocerebellar ataxia type 3 ,Autophagy ,Zebrafish ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.
- Published
- 2024
- Full Text
- View/download PDF
22. Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
- Author
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National Ataxia Foundation and University of California, Los Angeles
- Published
- 2023
23. Global DNA methylation is not elevated in blood samples from Machado-Joseph disease mutation carriers
- Author
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Luís Teves, Ana Rosa Vieira Melo, Ana F. Ferreira, Mafalda Raposo, Carolina Lemos, Conceição Bettencourt, and Manuela Lima
- Subjects
Machado-Joseph disease ,SCA3 ,polyq disorders ,DNA methylation ,epigenetic modifiers ,Genetics ,QH426-470 - Abstract
Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.
- Published
- 2024
- Full Text
- View/download PDF
24. Recurrent divergence-insufficiency esotropia in Machado-Joseph disease (spinocerebellar ataxia type 3).
- Author
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Stallworth, Jeannette Y, Rasool, Nailyn, and Indaram, Maanasa
- Subjects
Divergence-insufficiency esotropia ,Machado-Joseph disease ,Spinocerebellar ataxia ,Brain Disorders ,Clinical Research ,Neurosciences - Abstract
PurposeTo describe a case of incomitant divergence insufficiency esotropia in the setting of Machado-Joseph disease (spinocerebellar ataxia type 3) that recurred completely within one week after augmented bilateral medial rectus recession.ObservationsA 53-year-old female with a history of Machado-Joseph disease presented with horizontal diplopia primarily at distance consistent with divergence insufficiency esotropia. Augmented bilateral medial rectus recessions were performed which initially produced orthotropia, but recurrence of the esodeviation to the full preoperative amount occurred by post-operative week one. The patient subsequently underwent bilateral lateral rectus resections with excellent result.Conclusions and importanceDivergence insufficiency is common in the spinocerebellar ataxia variants and is thought to be secondary to atrophy of brainstem structures involved in the control of ocular vergence. Strabismus surgery in these patients may be complicated by limited response or even rapid regression despite augmented surgery as suggested for divergence insufficiency in the setting of neurologic disease. Patients should be counseled on these risks as well as the potential for multiple procedures in order to achieve surgical success.
- Published
- 2022
25. Spermidine treatment: induction of autophagy but also apoptosis?
- Author
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Watchon, Maxinne, Wright, Amanda L., Ahel, Holly I., Robinson, Katherine J., Plenderleith, Stuart K., Kuriakose, Andrea, Yuan, Kristy C., and Laird, Angela S.
- Subjects
- *
SPERMIDINE , *AUTOPHAGY , *TRINUCLEOTIDE repeats , *SPINOCEREBELLAR ataxia , *ANIMAL disease models , *GLUTAMINE , *POLYAMINES - Abstract
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
26. The vestibular symptomatology of Machado-Joseph Disease.
- Author
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Elyoseph, Zohar, Geisinger, Dario, Zaltzman, Roy, Mintz, Matti, and Gordon, Carlos R.
- Subjects
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SYMPTOMS , *BECK Anxiety Inventory , *VESTIBULO-ocular reflex , *CEREBELLAR ataxia , *VERTIGO - Abstract
BACKGROUND: Machado Joseph Disease (MJD) is an autosomal dominant neurodegenerative disease. In previous studies, we described significant bilateral horizontal Vestibulo-Ocular Reflex (VOR) deficit within this population without any reference to the presence of vestibular symptomatology. OBJECTIVE: To evaluate whether, beyond cerebellar ataxia complaints, MJD patients have typical vestibular symptomatology corresponding to the accepted diagnostic criteria of Bilateral Vestibulopathy (BVP) according to the definition of the International Barany Society of Neuro-Otology. METHODS: Twenty-one MJD, 12 clinically stable chronic Unilateral Vestibulopathy (UVP), 15 clinically stable chronic BVP, and 22 healthy Controls underwent the video Head Impulse Test (vHIT) evaluating VOR gain and filled out the following questionnaires related to vestibular symptomatology: The Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS) and the Beck Anxiety Inventory (BAI). RESULTS: The MJD group demonstrated significant bilateral vestibular impairment with horizontal gain less than 0.6 in 71% of patients (0.54±0.17). Similar to UVP and BVP, MJD patients reported a significantly higher level of symptoms than Controls in the DHI, ABC, VVS, and BAI questionnaires. CONCLUSIONS: MJD demonstrated significant VOR impairment and clinical symptoms typical of BVP. We suggest that in a future version of the International Classification of Vestibular Disorders (ICVD), MJD should be categorized under a separate section of central vestibulopathy with the heading of bilateral vestibulopathy. The present findings are of importance regarding the clinical diagnosis process and possible treatment based on vestibular rehabilitation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
27. Cognitive-affective manifestations since premanifest phases of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.
- Author
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Bolzan, Gabriela, Müller Eyng, Maria E., Leotti, Vanessa B., Saraiva-Pereira, Maria L., and Jardim, Laura B.
- Subjects
SPINOCEREBELLAR ataxia ,COGNITION disorders ,COGNITIVE ability ,SOCIAL perception ,NEUROPSYCHIATRY - Published
- 2024
- Full Text
- View/download PDF
28. Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.
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Watchon, Maxinne, Robinson, Katherine J., Luu, Luan, An, Yousun, Yuan, Kristy C., Plenderleith, Stuart K., Cheng, Flora, Don, Emily K., Nicholson, Garth A., Lee, Albert, and Laird, Angela S.
- Abstract
Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin‐3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH‐SY5Y cells and transgenic zebrafish expressing human ataxin‐3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH‐SY5Y cells were found to contain high molecular weight ataxin‐3 species and detergent‐insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin‐3 aggregates and presence of high molecular weight ataxin‐3 in an autophagy‐dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin‐3 protein species in the transgenic SCA3 zebrafish. Co‐treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy‐dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB‐treated and untreated SCA3 SH‐SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in vitro and in vivo. While our results suggested that this activity may involve activity of a PKA/AMPK‐dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Functional impact of bilateral vestibular loss and the unexplained complaint of oscillopsia
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Dario Geisinger, Zohar Elyoseph, Roy Zaltzman, Matti Mintz, and Carlos R. Gordon
- Subjects
bilateral vestibular areflexia ,oscillopsia ,Machado–Joseph disease ,peripheral vestibular and central disorders ,saccades ,spatial orientation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
IntroductionThe vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia.MethodsParticipants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado–Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center.ResultsAmong the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test.DiscussionEven though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it.
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- 2024
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30. Chinese Medicine WT for Spinocerebellar Ataxia Type 3
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Chiu Chung Min, Adjunct Physician
- Published
- 2023
31. Specific Biomarkers in Spinocerebellar Ataxia Type 3: A Systematic Review of Their Potential Uses in Disease Staging and Treatment Assessment
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Alexandra E. Soto-Piña, Caroline C. Pulido-Alvarado, Jaroslaw Dulski, Zbigniew K. Wszolek, and Jonathan J. Magaña
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spinocerebellar ataxia type 3 ,Machado–Joseph disease ,biomarkers ,neurofilament light chain ,PolyQ-ATXN3 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one.
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- 2024
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32. Treatment of Transcranial Alternating Current Stimulation(tACS)on Cerebellar Ataxia
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Ning Wang, MD., PhD., Director
- Published
- 2022
33. Machado Joseph-Disease Is Rare in the Peruvian Population.
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Cornejo-Olivas, Mario, Solis-Ponce, Lesly, Araujo-Aliaga, Ismael, Milla-Neyra, Karina, Ortega, Olimpio, Illanes-Manrique, Maryenela, Mazzetti, Pilar, Manrique-Enciso, Carla, Cubas-Montecino, Diana, Saraiva-Pereira, Maria Luiza, Jardim, Laura B., and Sarapura-Castro, Elison
- Subjects
- *
CEREBELLUM degeneration , *SPINOCEREBELLAR ataxia , *CEREBELLAR ataxia , *GENE frequency , *HINTERLAND , *TERTIARY care , *HAPLOTYPES - Abstract
Spinocerebellar ataxia type 3 or Machado-Joseph disease (MJD/SCA3) is the most prevalent autosomal dominant cerebellar ataxia worldwide, but its frequency varies by geographic region. We describe MJD/SCA3 patients diagnosed in a tertiary healthcare institution in Peru. In a cohort of 341 individuals (253 probands) with clinical ataxia diagnosis, seven MJD/SCA3 probands were identified and their pedigrees extended, detecting a total of 18 MJD/SCA3 cases. Out of 506 alleles from all probands from this cohort, the 23-CAG repeat was the most common ATXN3 allele (31.8%), followed by the 14-CAG repeat allele (26.1%). Normal alleles ranged from 12 to 38 repeats while pathogenic alleles ranged from 64 to 75 repeats. We identified 80 large normal (LN) alleles (15.8%). Five out of seven families declared an affected family member traced back to foreign countries (England, Japan, China, and Trinidad and Tobago). MJD/SCA3 patients showed ataxia, accompanied by pyramidal signs, dysarthria, and dysphagia as well as abnormal oculomotor movements. In conclusion, ATXN3 allelic distribution in non-MJD/SCA3 patients with ataxia is similar to the distribution in normal individuals around the world, whereas LN allele frequency reinforces no correlation with the frequency of MJD/SCA3. Evidence of any atypical MJD/SCA3 phenotype was not found. Furthermore, haplotypes are required to confirm the foreign origin of MJD/SCA3 in the Peruvian population. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
34. A model for the dynamics of expanded CAG repeat alleles: ATXN2 and ATXN3 as prototypes.
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Sena, Lucas Schenatto, Lemes, Renan Barbosa, Furtado, Gabriel Vasata, Saraiva-Pereira, Maria Luiza, and Jardim, Laura Bannach
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SPINOCEREBELLAR ataxia ,ALLELES ,HAPLOTYPES ,AGE of onset ,PROTOTYPES - Abstract
Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/ MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
35. Voxel-Based Morphometry and Relaxometry Demonstrate Macro- and Microstructural Damages in Spinocerebellar Ataxia Type 3.
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Gitaí, Lívia Leite Góes, Sobreira-Neto, Manoel Alves, Diniz, Paula Rejane Beserra, Éckeli, Alan Luiz, Fernandes, Regina Maria França, Marques Jr, Wilson, and Santos, Antonio Carlos
- Subjects
- *
VOXEL-based morphometry , *MEDULLA oblongata , *GRAY matter (Nerve tissue) , *WHITE matter (Nerve tissue) , *MAGNETIC resonance imaging - Abstract
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common SCA worldwide and comprises about 70% of SCA patients in Brazil. Magnetic resonance imaging (MRI) sequences have been used to describe microstructural abnormalities in many neurodegenerative diseases and helped to reveal the excessive iron accumulation in many of these conditions. This study aimed to characterize brain changes in gray matter (GM) and white matter (WM), detected by voxel-based morphometry (VBM) and relaxometry in patients with SCA3/MJD. A group of consecutive individuals, older than 18 years of age, with symptomatic and genetically proven SCA3/MJD diagnosed, and a control group, were submitted to clinical evaluation and MRI. The images were analyzed using VBM technique and relaxometry. The global assessment of brain volume by region of interest showed a significant difference in GM between SCA3/MJD and normal controls. VBM was used to locate these volumetric changes and it revealed a noticeable difference in the GM of the cerebellum and the brainstem. The global assessment of the brain by relaxometry also showed a significant difference in the comparison of GM between SCA3/MJD and normal controls, detecting noticeable prolongation of T2 time in the medulla oblongata (p < 0.001) and in the pontine tegmentum (p = 0.009) in SCA3/MJD compared to control group. Our study suggests that SCA3/MJD affects the macrostructure of the cerebellum and brainstem and microstructure of pons and medulla oblongata GM, as already demonstrated in the pathological study. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. Mitochondrial Dysfunction and Decreased Cytochrome c in Cell and Animal Models of Machado–Joseph Disease.
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Almeida, Filipa, Ferreira, Ildete L., Naia, Luana, Marinho, Daniela, Vilaça-Ferreira, Ana Catarina, Costa, Marta D., Duarte-Silva, Sara, Maciel, Patrícia, and Rego, A. Cristina
- Subjects
- *
HUNTINGTIN protein , *CYTOCHROME c , *ANIMAL disease models , *MITOCHONDRIA , *MEMBRANE potential , *MITOCHONDRIAL membranes - Abstract
Mitochondrial dysfunction has been described in many neurodegenerative disorders; however, there is less information regarding mitochondrial deficits in Machado–Joseph disease (MJD), a polyglutamine (polyQ) disorder caused by CAG repeat expansion in the ATXN3 gene. In the present study, we characterized the changes in mitochondrial function and biogenesis markers in two MJD models, CMVMJD135 (MJD135) transgenic mice at a fully established phenotype stage and tetracycline-regulated PC6-3 Q108 cell line expressing mutant ataxin-3 (mATXN3). We detected mATXN3 in the mitochondrial fractions of PC6-3 Q108 cells, suggesting the interaction of expanded ATXN3 with the organelle. Interestingly, in both the cerebella of the MJD135 mouse model and in PC6-3 Q108 cells, we found decreased mitochondrial respiration, ATP production and mitochondrial membrane potential, strongly suggesting mitochondrial dysfunction in MJD. Also, in PC6-3 Q108 cells, an additional enhanced glycolytic flux was observed. Supporting the functional deficits observed in MJD mitochondria, MJD135 mouse cerebellum and PC6-3 Q108 cells showed reduced cytochrome c mRNA and protein levels. Overall, our findings show compromised mitochondrial function associated with decreased cytochrome c levels in both cell and animal models of MJD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
37. The Ubiquitin–Proteasome System and Cerebellar Developmental Disease
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Vriend, Jerry, Jiao, Xiaodan, Manto, Mario, Series Editor, and Marzban, Hassan, editor
- Published
- 2023
- Full Text
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38. Repetitive Transcranial Magnetic Stimulation in SCA3 Patients
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Ning Wang, MD., PhD., National Natural Science Foundation of China(U1505222)
- Published
- 2022
39. Efficacy Of Oral Trehalose In Spinocerebellar Ataxia 3
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Radboud University Medical Center and Dr Norlinah Mohamed Ibrahim, Professor
- Published
- 2022
40. Production of Spinocerebellar Ataxia Type 3 Model Mice by Intravenous Injection of AAV-PHP.B Vectors
- Author
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Ayumu Konno, Yoichiro Shinohara, and Hirokazu Hirai
- Subjects
adeno-associated virus ,AAV ,AAV-PHP.B ,Spinocerebellar ataxia type 3 ,SCA3 ,Machado–Joseph disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We aimed to produce a mouse model of spinocerebellar ataxia type 3 (SCA3) using the mouse blood–brain barrier (BBB)-penetrating adeno-associated virus (AAV)-PHP.B. Four-to-five-week-old C57BL/6 mice received injections of high-dose (2.0 × 1011 vg/mouse) or low-dose (5.0 × 1010 vg/mouse) AAV-PHP.B encoding a SCA3 causative gene containing abnormally long 89 CAG repeats [ATXN3(Q89)] under the control of the ubiquitous chicken β-actin hybrid (CBh) promoter. Control mice received high doses of AAV-PHP.B encoding ATXN3 with non-pathogenic 15 CAG repeats [ATXN3(Q15)] or phosphate-buffered saline (PBS) alone. More than half of the mice injected with high doses of AAV-PHP.B encoding ATXN3(Q89) died within 4 weeks after the injection. No mice in other groups died during the 12-week observation period. Mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89) exhibited progressive motor uncoordination starting 4 weeks and a shorter stride in footprint analysis performed at 12 weeks post-AAV injection. Immunohistochemistry showed thinning of the molecular layer and the formation of nuclear inclusions in Purkinje cells from mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89). Moreover, ATXN3(Q89) expression significantly reduced the number of large projection neurons in the cerebellar nuclei to one third of that observed in mice expressing ATXN3(Q15). This AAV-based approach is superior to conventional methods in that the required number of model mice can be created simply by injecting AAV, and the expression levels of the responsible gene can be adjusted by changing the amount of AAV injected. Moreover, this method may be applied to produce SCA3 models in non-human primates.
- Published
- 2024
- Full Text
- View/download PDF
41. Clinical Trial Readiness for SCA1 and SCA3 (READISCA)
- Author
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University of Michigan, University of Minnesota, University of Utah, University of California, Los Angeles, University of Chicago, University of South Florida, Harvard University, Johns Hopkins University, University of Florida, Columbia University, Emory University, University of California, San Francisco, University of Alabama at Birmingham, University of Colorado, Denver, University of Rochester, Stanford University, Northwestern University, German Center for Neurodegenerative Diseases (DZNE), Institut de Recherche sur la Moelle épinière et l'Encéphale, University of Pennsylvania, Ohio State University, University of Iowa, and Tetsuo Ashizawa, MD, HMRI Neurosciences Principal Investigator & Multicenter Lead Investigator
- Published
- 2022
42. A model for the dynamics of expanded CAG repeat alleles: ATXN2 and ATXN3 as prototypes
- Author
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Lucas Schenatto Sena, Renan Barbosa Lemes, Gabriel Vasata Furtado, Maria Luiza Saraiva-Pereira, and Laura Bannach Jardim
- Subjects
allele dynamics ,Machado-Joseph disease ,mathematical model ,polyglutamine diseases ,spinocerebellar ataxia type 2 ,spinocerebellar ataxia type 3 ,Genetics ,QH426-470 - Abstract
Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood.Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last.Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed.Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges.Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.
- Published
- 2023
- Full Text
- View/download PDF
43. Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP 3 R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3.
- Author
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Cunha-Garcia, Daniela, Monteiro-Fernandes, Daniela, Correia, Joana Sofia, Neves-Carvalho, Andreia, Vilaça-Ferreira, Ana Catarina, Guerra-Gomes, Sónia, Viana, João Filipe, Oliveira, João Filipe, Teixeira-Castro, Andreia, Maciel, Patrícia, and Duarte-Silva, Sara
- Subjects
- *
SPINOCEREBELLAR ataxia , *HUNTINGTIN protein , *LABORATORY mice , *ANIMAL disease models , *DISEASE progression , *INOSITOL , *RYANODINE receptors - Abstract
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
44. Diagnostic Delay of Hereditary Ataxias in Brazil: the Case of Machado-Joseph Disease.
- Author
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dos Santos Pinheiro, Jordânia, Sena, Lucas Schenatto, Donis, Karina Carvalho, Furtado, Gabriel Vasata, Saraiva-Pereira, Maria Luiza, and Jardim, Laura Bannach
- Subjects
- *
DELAYED diagnosis , *CEREBELLUM degeneration , *SPINOCEREBELLAR ataxia , *AGE of onset , *DIGITAL inclusion , *PUBLIC hospitals - Abstract
Background: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a rare disease with diagnosis offered by the Unified Health System in Brazil. Our aim was to investigate the diagnostic delay in an interval of 23 years in a public university hospital, and some potentially determining factors. Methods: A retrospective review of the medical records of subjects identified at our institution between 1999 and 2017 was carried out, including residents of Rio Grande do Sul. The diagnostic delay was equivalent to the difference between age at onset of symptoms and age at molecular diagnosis. Calendar years, educational level, sex, distance between the household and the clinics, age and being the index case were studied as modifying factors. Results: SCA3/MJD had a median diagnostic delay of 5 years. Index cases had delays of 6 versus 4 years (p<0.001) for subsequent family members. Delay correlated with age (rho=0.346, p<0.001), but not with age at disease onset (rho=0.005, p=0.91). No change was observed with the level of education of individuals or with the distance between household and hospital from 1999 to 2017. Discussion: The diagnostic delay of SCA3/MJD is high in our region, where its occurrence has been reported for years. Failure to change the delay over the years suggests ineffective dissemination to the population, but a smaller lag among younger people can portray the effect of digital inclusion. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
45. Regional and age-dependent changes in ubiquitination in cellular and mouse models of spinocerebellar ataxia type 3.
- Author
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Haiyang Luo, Todi, Sokol V., Paulson, Henry L., and Costa, Maria do Carmo
- Subjects
SPINOCEREBELLAR ataxia ,UBIQUITINATION ,LABORATORY mice ,TRANSGENIC mice ,DEUBIQUITINATING enzymes ,CELL death - Abstract
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in the ATXN3 gene that encodes an expanded tract of polyglutamine in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murine Atxn3 or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-old Atxn3 knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48-Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
46. Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics.
- Author
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Paulino, Rodrigo and Nóbrega, Clévio
- Subjects
- *
SPINOCEREBELLAR ataxia , *AUTOPHAGY , *PROTEIN conformation , *GENETIC transcription regulation , *THERAPEUTICS - Abstract
Machado–Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
47. Autophagic vacuolar myopathy involving the phenotype of spinocerebellar ataxia type 3.
- Author
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Li, Jingjing, Peng, Yun, Tang, Jincai, Li, Menghua, Zhu, Min, Zhou, Meihong, Fang, Pu, and Hong, Daojun
- Subjects
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SPINOCEREBELLAR ataxia , *INCLUSION body myositis , *SENSORY ataxia , *AUTOPHAGY , *MUSCLE diseases , *NEMALINE myopathy - Abstract
Spinocerebellar ataxia type 3 (SCA3) is a form of autosomal dominant cerebellar ataxia with a wide range of clinical manifestations, including ataxia and pyramidal and extrapyramidal signs. A few SCA3 patients have been noticed to be predisposed to the development of inclusion body myositis. It is still unknown whether muscle can be primarily involved in the pathogenesis of SCA3. This study reported an SCA3 family in which the index patient initially presented with parkinsonism, sensory ataxia, and distal myopathy but the absence of cerebellar and pyramidal symptoms. The clinical and electrophysiological studies implied a possible combination of distal myopathy and sensory–motor neuropathy or neuronopathy. MRI muscle showed selective fat infiltration and absence of denervated edema‐like changes, indicating the distal muscle weakness had a myopathic origin. Muscle pathology showed the myopathic involvement, besides neurogenic involvement, characterized by chronic myopathic changes with multiple autophagic vacuoles. Genetic screening revealed expanded CAG of 61 repeats in the ATXN3 gene, which showed co‐segregation in the family. Besides the neurogenic origin, the myopathic origin may be partly attributed to the limb weakness of SCA3 patients, which expands the spectrum of the clinical manifestation of SCA3. [ABSTRACT FROM AUTHOR]
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- 2023
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48. Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies.
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Santos, Carolina, Malheiro, Sofia, Correia, Manuel, and Damásio, Joana
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GENE silencing , *CRISPRS , *RNA interference , *GENE therapy , *ELECTROPORATION - Abstract
Introduction: Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of in vivo studies investigating the efficacy and safety profile of GSTs in HCAs. Methods: A structured PubMed® search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article. Results: The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed. Conclusion: The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype in vivo. Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2. [ABSTRACT FROM AUTHOR]
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- 2023
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49. Deficiency in classical nonhomologous end-joining–mediated repair of transcribed genes is linked to SCA3 pathogenesis
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Chakraborty, Anirban, Tapryal, Nisha, Venkova, Tatiana, Mitra, Joy, Vasquez, Velmarini, Sarker, Altaf H, Duarte-Silva, Sara, Huai, Weihan, Ashizawa, Tetsuo, Ghosh, Gourisankar, Maciel, Patricia, Sarkar, Partha S, Hegde, Muralidhar L, Chen, Xu, and Hazra, Tapas K
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Neurodegenerative ,Rare Diseases ,Brain Disorders ,Neurosciences ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,80 and over ,Animals ,Animals ,Genetically Modified ,Ataxin-3 ,Brain ,Cell Line ,DNA Breaks ,Double-Stranded ,DNA End-Joining Repair ,DNA Repair Enzymes ,Disease Models ,Animal ,Drosophila ,Female ,Gene Knockdown Techniques ,Humans ,Induced Pluripotent Stem Cells ,Machado-Joseph Disease ,Male ,Mice ,Middle Aged ,Mutation ,Peptides ,Phosphotransferases (Alcohol Group Acceptor) ,RNA Polymerase II ,RNA ,Small Interfering ,Repressor Proteins ,ATXN3 ,DNA double-strand break repair ,PNKP ,RNA-templated TC-NHEJ ,spinocerebellar ataxia type-3 - Abstract
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by CAG (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene. We have shown previously that ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3'-phosphatase (PNKP) activity. Here, we report that ATXN3 associates with RNA polymerase II (RNAP II) and the classical nonhomologous end-joining (C-NHEJ) proteins, including PNKP, along with nascent RNAs under physiological conditions. Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3'-phosphate-containing terminally gapped, linearized reporter plasmid. The missing sequence at the terminal break site was restored in the recircularized plasmid in control cells by using the endogenous homologous transcript as a template, indicating ATXN3's role in PNKP-mediated error-free C-NHEJ. Furthermore, brain extracts from SCA3 patients and mice show significantly lower PNKP activity, elevated p53BP1 level, more abundant strand-breaks in the transcribed genes, and degradation of RNAP II relative to controls. A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.
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- 2020
50. The impact of ethnicity on the clinical presentations of spinocerebellar ataxia type 3.
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Gan, Shi-Rui, Figueroa, Karla, Xu, Hao-Ling, Perlman, Susan, Wilmot, George, Gomez, Christopher, Schmahmann, Jeremy, Paulson, Henry, Shakkottai, Vikram, Ying, Sarah, Zesiewicz, Theresa, Bushara, Khalaf, Geschwind, Michael, Xia, Guangbin, Subramony, S, Rosenthal, Liana, Ashizawa, Tetsuo, Pulst, Stefan, Wang, Ning, and Kuo, Sheng-Han
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Cerebellum ,Depression ,Ethnicity ,Neurodegeneration ,Spinocerebellar ataxia type 3 ,Adult ,Black or African American ,Age of Onset ,Aged ,Asian ,Asian People ,Depression ,Female ,Humans ,Longitudinal Studies ,Machado-Joseph Disease ,Male ,Middle Aged ,Severity of Illness Index ,White People - Abstract
BACKGROUND: For a variety of sporadic neurodegenerative diseases such as Alzheimers disease, Parkinsons disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied. METHODS: We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia). RESULTS: We found that Asians had significantly later AAO, compared to Caucasians (β = 4.75, p = 0.000) and to African Americans (β = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (β = 3.81, p = 0.004) and Asians (β = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (β = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia. CONCLUSIONS: Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.
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- 2020
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