# An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model

## TL;DR

This study shows that a specific mutation in the ATAXIN1 gene worsens Multiple Sclerosis symptoms in mice by impairing its protective role against immune damage.

## Contribution

The study reveals that polyglutamine expansion in ATAXIN1 leads to a loss-of-function effect that exacerbates Multiple Sclerosis pathology in an EAE mouse model.

## Key findings

- Loss-of-function of wild-type Atxn1 in mutant mice leads to increased demyelination, oligodendrocyte loss, and axon degeneration.
- Neurotoxic astrocytes are activated during acute EAE but not in chronic stages in mutant mice.
- Mutant mice show enhanced immune cell infiltration into lesions compared to controls.

## Abstract

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.

Hemizygous Atxn1 (Atxn12Q/−) mice or f-ATXN1146Q/2Q, 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 Atxn12Q/− and f-ATXN1146Q/2Q mice.

Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn12Q/− and f-ATXN1146Q/2Q 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.

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.