Sacs R272C missense homozygous mice develop an ataxia phenotype

Roxanne Larivière,Nicolas Sgarioto,Alanna J Watt,Rébecca Gaudet,Brenda Toscano Márquez,Karine Choquet,R Anne Mckinney,Bernard Brais

doi:10.1186/s13041-019-0438-3

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 200 SACS mutations have been identified. Most mutations lead to a complete loss of a sacsin, a large 520 kD protein, although some missense mutations are associated with low levels of sacsin expression. We previously showed that Sacs knock-out mice demonstrate early-onset ataxic phenotype with neurofilament bundling in many neuronal populations. To determine if the preservation of some mutated sacsin protein resulted in the same cellular and behavioral alterations, we generated mice expressing an R272C missense mutation, a homozygote mutation found in some affected patients. Though SacsR272C mice express 21% of wild type brain sacsin and sacsin is found in many neurons, they display similar abnormalities to Sacs knock-out mice, including the development of an ataxic phenotype, reduced Purkinje cell firing rates, and somatodendritic neurofilament bundles in Purkinje cells and other neurons. Together our results support that Sacs missense mutation largely lead to loss of sacsin function.

Highlights

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) was first described in the French Canadian population in 1978 [1]
Here we report that expression of mutated R272C sacsin protein in mice leads to a similar and potentially milder phenotype than that previously characterized in the Sacs−/− animals [23]
We did not investigate R272C mutant sacsin protein folding, we did identify a significant decrease in mutant protein levels on Western blot and immunohistochemical labelings from animal brains

Summary

Introduction

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) was first described in the French Canadian population in 1978 [1]. As it was observed for Sacs−/− mice [22], Nissl-stained sections from 45 day-old SacsR272C demonstrate normal cerebellar structure and lobulation compared to age-matched controls (Fig. 3a,b).

Results

Conclusion