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Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease.
Nascimento-Ferreira, Isabel; Santos-Ferreira, Tiago; Sousa-Ferreira, Lígia; Auregan, Gwennaëlle; Onofre, Isabel; Alves, Sandro; Dufour, Noëlle; Colomer Gould, Veronica F; Koeppen, Arnulf; Déglon, Nicole; Pereira de Almeida, Luís.
Afiliación
  • Nascimento-Ferreira I; Center for Neurosciences and Cell Biology, Faculty of Pharmacy, Department of Life Sciences, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal.
Brain ; 134(Pt 5): 1400-15, 2011 May.
Article en En | MEDLINE | ID: mdl-21478185
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Represoras / Autofagia / Proteínas Nucleares / Enfermedad de Machado-Joseph / Proteínas Reguladoras de la Apoptosis / Proteínas de la Membrana / Mutación / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Brain Año: 2011 Tipo del documento: Article País de afiliación: Portugal

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Represoras / Autofagia / Proteínas Nucleares / Enfermedad de Machado-Joseph / Proteínas Reguladoras de la Apoptosis / Proteínas de la Membrana / Mutación / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Brain Año: 2011 Tipo del documento: Article País de afiliación: Portugal