Back to Search
Start Over
Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2015 Jan 01; Vol. 24 (1), pp. 100-17. Date of Electronic Publication: 2014 Aug 20. - Publication Year :
- 2015
-
Abstract
- 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 α5 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.<br /> (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Ataxin-3
Cell Differentiation
Cells, Cultured
Ganglia, Spinal cytology
Ganglia, Spinal metabolism
HEK293 Cells
Hippocampus cytology
Hippocampus metabolism
Humans
Integrin alpha5 metabolism
Mice
PC12 Cells
Proteasome Endopeptidase Complex metabolism
Rats
Rats, Wistar
Nerve Tissue Proteins metabolism
Neurons metabolism
Nuclear Proteins metabolism
Peptides metabolism
Repressor Proteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25143392
- Full Text :
- https://doi.org/10.1093/hmg/ddu422