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Title: Fibroblasts of Machado Joseph Disease patients reveal autophagy impairment
Authors: Onofre, Isabel 
Mendonça, Nuno 
Lopes, Sara 
Nobre, Rui J. 
Melo, Joana Barbosa 
Carreira, Isabel Marques 
Januário, Cristina 
Gonçalves, António Freire 
Almeida, Luís Pereira de 
Issue Date: 22-Jun-2016
Publisher: Springer Nature
Project: CENTRO-07-ST24-FEDER-002006 
European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative, ModelPolyQ 
SynSpread, under the JPND-Joint Programme on Neurodegenerative Disease 
Richard Chin and Lily Lock Machado Joseph Disease Research Fund 
National Ataxia Foundation. 
Serial title, monograph or event: Scientific Reports
Volume: 6
Issue: 1
Abstract: Machado Joseph Disease (MJD) is the most frequent autosomal dominantly inherited cerebellar ataxia caused by the over-repetition of a CAG trinucleotide in the ATXN3 gene. This expansion translates into a polyglutamine tract within the ataxin-3 protein that confers a toxic gain-of-function to the mutant protein ataxin-3, contributing to protein misfolding and intracellular accumulation of aggregates and neuronal degeneration. Autophagy impairment has been shown to be one of the mechanisms that contribute for the MJD phenotype. Here we investigated whether this phenotype was present in patient-derived fibroblasts, a common somatic cell type used in the derivation of induced pluripotent stem cells and subsequent differentiation into neurons, for in vitro disease modeling. We generated and studied adult dermal fibroblasts from 5 MJD patients and 4 healthy individuals and we found that early passage MJD fibroblasts exhibited autophagy impairment with an underlying mechanism of decreased autophagosome production. The overexpression of beclin-1 on MJD fibroblasts reverted partially autophagy impairment by increasing the autophagic flux but failed to increase the levels of autophagosome production. Overall, our results provide a well-characterized MJD fibroblast resource for neurodegenerative disease research and contribute for the understanding of mutant ataxin-3 biology and its molecular consequences.
ISSN: 2045-2322
DOI: 10.1038/srep28220
Rights: openAccess
Appears in Collections:IIIUC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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