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TitleDominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells
Author(s)Carvalho, Andreia Alexandra Neves
Logarinho, Elsa
Freitas, Ana
Silva, Sara Duarte
Costa, Maria do Carmo
Fernandes, Anabela Silva
Martins, Margarida Isabel Barros Coelho
Serra, Sofia Cravino
Lopes, André Teixeira
Paulson, Henry L.
Heutink, Peter
Relvas, João B.
Maciel, P.
Issue date2015
PublisherOxford University Press
JournalHuman Molecular Genetics
Abstract(s)The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado–Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of a5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration.
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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