Browsing by Author "Couto, Filipa Lopes"
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- Modulation of a RBP as potential therapeutic strategy for SCA2Publication . Couto, Filipa Lopes; Nóbrega, ClévioSpinocerebellar ataxia type 2 (SCA2) is one of the nine polyglutamine disease (polyQ), characterized by an abnormally long expansion of the adenine-cytosine-guanine (CAG) trinucleotide within each respective disease-associated gene. PolyQ diseases are dominantly inherited neurodegenerative disorders in which, affected people experience a myriad of highly debilitating motor symptoms. SCA2 arises from a mutation within the coding region of the ATXN2 gene, which is translated into ataxin-2 protein bearing an abnormally long polyQ tract. This mutant protein is prone to aggregate and known to gain toxic function, which is in the basis for disrupting several molecular pathways, which ultimately lead to neuronal death, within specific brain region, including the pons and the cerebellum. Among other, these disrupted pathways might include aberrant RNA metabolism or even loss of cellular proteostasis. Unfortunately, there are no therapeutic options capable of preventing such pathways to became dysregulated, which mean that people affected by SCA2 have no therapies able to cure nor delay the disease progression, ultimately suffering a premature death. To understand whether reestablishing cellular proteostasis could, in fact mitigate SCA2-associated pathology we sought to evaluate the impact of expressing HSPA8, a crucial chaperone involved in the mechanism of proteome homeostasis. In this work we used both in vitro and in vivo approaches to assess whether HSPA8 expression was able prevent SCA2 pathology. We observed that in in vitro models of SCA2 and in an in vivo lentiviral model of this disease, HSPA8 expression was able to both prevent the number of ataxin-2 aggregates and at the same time preserve the neuronal tissue. This work suggests that the expression of HSPA8, a chaperone involved in the mechanism of cellular proteostasis, was able to mitigate SCA2-associated disease hallmarks. Therefore, HPSPA8 could represent a novel therapeutic target for SCA2.