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

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.

• Authors: Isabel Nascimento-Ferreira, Clévio Nóbrega, Ana Vasconcelos-Ferreira, Isabel Onofre, David Albuquerque, Célia Aveleira, Hirokazu Hirai, Nicole Déglon, Luís Pereira de Almeida
• Journal: Brain : a journal of neurology (Brain) Vol. 136 Issue Pt 7 Pg. 2173-88 (Jul 2013) ISSN: 1460-2156 [Electronic] England
• PMID: 23801739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Membrane Proteins
• Nerve Tissue Proteins
• Nuclear Proteins
• Peptides
• Repressor Proteins
• Green Fluorescent Proteins
• polyglutamine
• ATXN3 protein, human
• Ataxin-3

Topics

• Age Factors
• Analysis of Variance
• Animals
• Animals, Newborn
• Apoptosis Regulatory Proteins (genetics, metabolism, therapeutic use)
• Ataxin-3
• Autophagy (genetics)
• Beclin-1
• Cells, Cultured
• Cerebellum (cytology)
• Disease Models, Animal
• Dopamine and cAMP-Regulated Phosphoprotein 32 (metabolism)
• Female
• Gene Expression Regulation (genetics)
• Green Fluorescent Proteins (genetics)
• Humans
• Machado-Joseph Disease (complications, drug therapy, genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Motor Activity (drug effects, genetics)
• Nerve Degeneration (etiology, prevention & control)
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Peptides (genetics)
• Postural Balance (genetics)
• Psychomotor Performance (physiology)
• Repressor Proteins (genetics, metabolism)
• Sensation Disorders (etiology, genetics, metabolism)
• Transfection