ALS-Associated Ataxin 2 PolyQ Expansions Enhance Stress-Induced Caspase 3 Activation and Increase TDP-43 Pathological Modifications

摘要: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the loss of motor neurons. The degenerating neurons ALS patients are characterized accumulation cytoplasmic inclusions containing phosphorylated and truncated forms RNA-binding protein TDP-43. Ataxin 2 intermediate-length polyglutamine (polyQ) expansions were recently identified as risk factor for ALS; however, mechanism which they contribute to unknown. Here, we show that ataxin polyQ enhance stress-induced TDP-43 C-terminal cleavage phosphorylation in human cells. We also connect stress-dependent activation multiple caspases, including caspase 3. Caspase upstream since inhibitors block these pathological modifications. Analysis activated 3 revealed striking association with cases harboring expansions. These findings indicate defines new feature results provide mechanistic insight into how could ALS—by enhancing modifications via activation. Because longer associated different disease, spinocerebellar ataxia 2, help explain same can have distinct cellular consequences, ultimately resulting clinical features. Finally, effective at reducing modifications, this pathway be pursued therapeutic target ALS.