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Brain. 2013 Jul;136(Pt 7):2173-88. doi: 10.1093/brain/awt144.

Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease.

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1
Centre for Neuroscience and Cell Biology, University of Coimbra, 3004- 517 Coimbra, Portugal.

Abstract

Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease.

KEYWORDS:

ataxin-3; autophagy; beclin-1, Machado-Joseph disease, spinocerebellar ataxia type 3

PMID:
23801739
DOI:
10.1093/brain/awt144
[Indexed for MEDLINE]
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