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Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo
H Ikeda1, M Yamaguchi, S Sugai
1Department of Pharmacology, Kyoto University Faculty of Medicine, Japan.
Abstract:
Recently, we identified a novel gene, MJD1, which contains an expanded CAG triplet repeat in Machado-Joseph disease. Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded CAG repeats. Cell death occurs only when the CAG repeat is translated into polyglutamine residues, which apparently precipitate in large covalently modified forms. We also created ataxic transgenic mice by expressing the expanded polyglutamine stretch in Purkinje cells. Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions.
Insights
Researchers found that expanded CAG repeats in the MJD1 gene induce cell death by forming toxic polyglutamine aggregates. This discovery suggests a common cause for inherited neurodegenerative diseases linked to CAG expansions.
Area of Science:
- Neurogenetics
- Molecular Biology
- Cellular Pathology
Background:
- Machado-Joseph disease is a neurodegenerative disorder linked to the MJD1 gene.
- The MJD1 gene is characterized by an expanded CAG triplet repeat sequence.
Purpose of the Study:
- To investigate the role of expanded CAG repeats in MJD1 in cellular toxicity.
- To explore the mechanism of cell death induced by MJD1 gene expression.
- To develop an animal model for studying CAG repeat-associated neurodegeneration.
Main Methods:
- Induction of apoptosis in cultured cells expressing MJD1 gene fragments with expanded CAG repeats.
- Analysis of polyglutamine residue formation and aggregation.
- Creation of ataxic transgenic mice expressing expanded polyglutamine in Purkinje cells.
Main Results:
- Expression of MJD1 gene portions with expanded CAG repeats induced apoptosis in cultured cells.
- Cell death was dependent on the translation of CAG repeats into polyglutamine residues.
- Polyglutamine aggregates formed large, covalently modified structures.
- Transgenic mice expressing expanded polyglutamine in Purkinje cells exhibited ataxia.
Conclusions:
- Expanded polyglutamine stretches are a potential common etiological agent in inherited neurodegenerative diseases with CAG expansions.
- The MJD1 gene and its expanded CAG repeats play a crucial role in Machado-Joseph disease pathogenesis.
- Polyglutamine-induced cellular toxicity and neuronal dysfunction are key mechanisms in these disorders.