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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Analysis of Variance
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Animals
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Animals, Newborn
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis Regulatory Proteins / therapeutic use*
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Ataxin-3
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Autophagy / genetics
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Beclin-1
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Cells, Cultured
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Cerebellum / cytology
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Disease Models, Animal
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Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
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Female
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Humans
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Machado-Joseph Disease / complications
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Machado-Joseph Disease / drug therapy*
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Machado-Joseph Disease / genetics
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Machado-Joseph Disease / metabolism*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Membrane Proteins / therapeutic use*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / drug effects
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Motor Activity / genetics
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Nerve Degeneration / etiology
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Nerve Degeneration / prevention & control
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptides / genetics
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Postural Balance / genetics
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Psychomotor Performance / physiology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Sensation Disorders / etiology
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Sensation Disorders / genetics
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Sensation Disorders / metabolism
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Transfection
Substances
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Membrane Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Repressor Proteins
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Green Fluorescent Proteins
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polyglutamine
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ATXN3 protein, human
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Ataxin-3