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Connecting mutant Ataxin-2 and synaptic disfunction: are stress granules the link
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Mutant Ataxin-2 expression in aged animals aggravates neuropathological features associated with Spinocerebellar Ataxia type 2
Publication . Afonso, Inês T.; Lima, Patrícia; Conceição, André; Matos, Carlos A; Nóbrega, Clévio
Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.
Investigating the impact of stress granules in the pathogenesis of spinocerebellar ataxia type 2
Publication . Conceição, André; Nóbrega, Clévio; Carvalho, Ana Luísa; Matos, Carlos Adriano de
Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disease caused by an abnormally long cytosine-adenine-guanine (CAG) expansion mutaron within the coding region of the ATXN2 gene. This mutaron produces an ataxin-2 protein form, which bears an overexpanded glutamine tract with neurotoxic properres. Despite the efforts, the pathogenic mechanisms underlying neurodegeneraron in SCA2 are srll poorly understood, and no therapy is available to delay or stop disease progression. In this work, we invesrgated the impact of stress granules (SGs) in SCA2 pathogenesis. SGs are dynamic membraneless organelles formed during the integrated stress response (ISR) to aid cells in coping with stress. Among other biological funcrons, these structures are thought to serve as local stores of untranslated mRNAs, allowing cells to priorirze the translaron of stress-resolving factors while reducing the energerc burden of global translaron during crircal periods. Emerging evidence suggests that persistent SGs under chronic stress condirons may have deleterious effects, potenrally contriburng to cellular dysfuncron and disease pathogenesis. Moreover, recent studies suggest that the ISR is overacrvated in several neurodegenerarve diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal demenra, and Parkinson’s disease, potenrally promorng an exacerbated stress response and an aberrant formaron of SGs. Nevertheless, the role of SGs in the context of chronic stress and neurodegenerarve disorders, parrcularly in SCA2, is srll poorly addressed. Using both in vitro and in vivo models of SCA2, we observed that SGs assembly and disassembly differently modifies the pathological deficits associated with SCA2. Promorng the formaron of SGs within a limited rmeframe seems to have protecrve effects, while sustained inducron results in an exacerbated SCA2-associated phenotype, supporrng the hypothesis that chronic SGs persistence has deleterious effects. On the other hand, SGs sustained inhibiron seemed to have discrete deleterious effects. These findings suggest that SGs are cellular structures requiring a concerted and rghtly regulated control, and chronic
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Fundação para a Ciência e a Tecnologia
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2020.07892.BD