Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes

Area of Science:

• Neurogenetics
• Molecular Neurology
• Genomic Instability Disorders

Background:

• Spinocerebellar ataxia type 8 (SCA8) is a progressive neurodegenerative disorder linked to a CTG.CAG repeat expansion on chromosome 13q21.
• The pathogenicity of the SCA8 expansion has been debated due to variable penetrance and its presence in the general population.

Purpose of the Study:

• To investigate the pathogenic mechanisms of the SCA8 CTG.CAG repeat expansion.
• To determine if the SCA8 expansion causes a neurological phenotype in a mammalian model.

Main Methods:

• Isolation of the SCA8 expansion mutation using RAPID cloning.
• Analysis of a seven-generation kindred (MN-A family) to assess co-segregation and penetrance.
• Development and study of a mouse model expressing the SCA8 BAC-expansion construct.

Main Results:

• A mouse model with the SCA8 BAC-expansion developed a progressive neurological phenotype, demonstrating pathogenicity.
• Affected mice exhibited loss of cerebellar GABAergic inhibition and intranuclear inclusions (1C2-positive) in neurons.
• The SCA8 expansion is bidirectionally expressed, producing polyglutamine proteins (ATXN8) and non-coding transcripts (ATXN8OS), suggesting dual toxic gain-of-function mechanisms.

Conclusions:

• The SCA8 CTG.CAG repeat expansion is pathogenic, causing neurodegeneration through toxic gain-of-function at both RNA and protein levels.
• Bidirectional gene expression across pathogenic microsatellite expansions may be a common mechanism in other neurological disorders.