Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease.

Abstract

Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. Here we investigated the implication of autophagy, the major pathway for organelle and protein turnover, in the accumulation of mutant ataxin-3 aggregates and neurodegeneration found in Machado-Joseph disease and we assessed whether specific stimulation of this pathway could mitigate the disease. Using tissue from patients with Machado-Joseph disease, transgenic mice and a lentiviral-based rat model, we found an abnormal expression of endogenous autophagic markers, accumulation of autophagosomes and decreased levels of beclin-1, a crucial protein in the early nucleation step of autophagy. Lentiviral vector-mediated overexpression of beclin-1 led to stimulation of autophagic flux, mutant ataxin-3 clearance and overall neuroprotective effects in neuronal cultures and in a lentiviral-based rat model of Machado-Joseph disease. These data demonstrate that autophagy is a key degradation pathway, with beclin-1 playing a significant role in alleviating Machado-Joseph disease pathogenesis.

DOI: 10.1093/brain/awr047

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@article{NascimentoFerreira2011OverexpressionOT, title={Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease.}, author={Isabel Nascimento-Ferreira and Tiago F. Santos-Ferreira and L{\'i}gia Sousa-Ferreira and Gwenna{\"{e}lle Aur{\'e}gan and Isabel Onofre and Sandro Alves and No{\"{e}lle Dufour and Veronica F Colomer Gould and Arnulf Koeppen and Nicole Deglon and Lu{\'i}s Pereira de Almeida}, journal={Brain : a journal of neurology}, year={2011}, volume={134 Pt 5}, pages={1400-15} }