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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Enhancement of Autophagy and Solubilization of Ataxin-2 Alleviate Apoptosis in Spinocerebellar Ataxia Type 2 Patient Cells

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  1. A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia

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  2. SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy

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  3. The role of the cerebellum in multiple sclerosis

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  4. Cerebellar cytokine expression in a rat model for fetal asphyctic preconditioning and perinatal asphyxia

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  5. Localization of CGRP receptor components, CGRP, and receptor binding sites in human and rhesus cerebellar cortex

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  1. Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

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  2. Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene

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  3. Mania triggered by levodopa treatment in a patient with frontotemporal dementia caused by A C9orf72 repeat expansion: A case report

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  4. Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia

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  5. Early Intrathecal T Helper 17.1 Cell Activity in Huntington Disease

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Spinocerebellar ataxia type 2 (SCA2), a rare polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene, exhibits common cellular phenotypes with other neurodegenerative disorders, including oxidative stress and mitochondrial dysfunction. Here, we show that SCA2 patient cells exhibit higher levels of caspase-8- and caspase-9-mediated apoptotic activation than control cells, cellular phenotypes that we find to be exacerbated by reactive oxygen species (ROS) and inhibition of autophagy. We also suggest that oligomerization of mutant ataxin-2 protein is likely to be the cause of the observed cellular phenotypes by causing inhibition of autophagy and by inducing ROS generation. Finally, we show that removal of ataxin-2 oligomers, either by increasing autophagic clearance or by oligomer dissolution, appears to alleviate the cellular phenotypes. Our results suggest that oligomerized ataxin-2 and oxidative stress affect autophagic clearance in SCA2 cells, contributing to the pathophysiology, and that activation of autophagy or clearance of oligomers may prove to be effective therapeutic strategies.

Original languageEnglish
JournalCerebellum
Volume19
Issue number2
Pages (from-to)165-181
Number of pages17
ISSN1473-4222
DOIs
Publication statusPublished - 1 Apr 2020

    Research areas

  • Ataxia, Autophagy, Neurodegenerative disease, Polyglutamine disease

ID: 59246740