title: 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.
authors.affiliation: Center for Neurosciences and Cell Biology, Faculty of Pharmacy, Department of Life Sciences, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.forename: Tiago
authors.initials: T
authors.lastname: Santos-Ferreira
authors.forename: Lígia
authors.initials: L
authors.lastname: Sousa-Ferreira
authors.forename: Gwennaëlle
authors.initials: G
authors.lastname: Auregan
authors.forename: Isabel
authors.initials: I
authors.lastname: Onofre
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.forename: Noëlle
authors.initials: N
authors.lastname: Dufour
authors.forename: Veronica F
authors.initials: VF
authors.lastname: Colomer Gould
authors.forename: Arnulf
authors.initials: A
authors.lastname: Koeppen
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000067699:Ataxin-3; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D014162:Transfection / Q000379:methods; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C518959:ATG16L1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C092341:ATXN3 protein, human; D000067699:Ataxin-3