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Updated: May 13, 2025
A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia
Published on: May 21, 2010
An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in
Gourango Talukdar1, Lisa Duvick1, Praseuth Yang1
1University of Minnesota.
Background And Objectives:
Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model.
Methods:
Hemizygous Atxn1 (Atxn1 ) mice or f-ATXN1 , heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human ATXN1 gene, were injected with myelin oligodendrocytes glycoprotein (MOG35 - 55) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in Atxn1 and f-ATXN1 mice.
Results:
Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn1 and f-ATXN1 mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice.
Discussion:
These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1's ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.
