Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells

Autor: Sara Duarte-Silva, Ana Freitas, João B. Relvas, Patrícia Maciel, Elsa Logarinho, Margarida Isabel Barros Coelho Martins, Anabela Silva-Fernandes, Maria do Carmo Costa, Peter Heutink, André T. Lopes, Andreia Neves-Carvalho, Henry L. Paulson, Sofia Cravino Serra
Přispěvatelé: Universidade do Minho
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Cellular differentiation
metabolism [Hippocampus]
Integrin alpha5
Hippocampus
PC12 Cells
Small hairpin RNA
Mice
Ganglia
Spinal
Atxn3 protein
mouse
metabolism [Peptides]
metabolism [Transcription Factors]
Ataxin-3
Genetics (clinical)
Cells
Cultured
metabolism [Repressor Proteins]
Neurons
biology
Neurodegeneration
Nuclear Proteins
Cell Differentiation
General Medicine
Articles
3. Good health
Cell biology
metabolism [Neurons]
metabolism [Integrin alpha5]
Atxn3 protein
rat
metabolism [Nuclear Proteins]
congenital
hereditary
and neonatal diseases and abnormalities
Proteasome Endopeptidase Complex
Integrin
Nerve Tissue Proteins
ddc:570
Genetics
medicine
Gene silencing
Animals
Humans
metabolism [Proteasome Endopeptidase Complex]
Rats
Wistar
Molecular Biology
Science & Technology
metabolism [Nerve Tissue Proteins]
cytology [Ganglia
Spinal]
HEK 293 cells
ATXN3 protein
human
medicine.disease
Rats
Repressor Proteins
HEK293 Cells
Ataxin
cytology [Hippocampus]
Immunology
Neuron differentiation
biology.protein
Peptides
polyglutamine
metabolism [Ganglia
Spinal]
Transcription Factors
Zdroj: Human molecular genetics 24(1), 100-117 (2014). doi:10.1093/hmg/ddu422
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
DOI: 10.1093/hmg/ddu422
Popis: 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.
National Institutes of Health (NIH) ‘(R01NS038712)
Fundação para a Ciência e a Tecnologia (FCT) and COMPETE through the project ‘(PTDC/SAU-GMG/ 101572/2008)
Fundação para a Ciência e a Tecnologia (FCT) - fellowships SFRH/BD/51059/2010, SFRH/BD/ 78388/2011 and SFRH/BPD/91562/2012
Databáze: OpenAIRE
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