Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration.

Jaya Bagaria,Seong Soo A An,Eva Bagyinszky

doi:10.3390/ijms23010552

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

Highlights

Sacsin (SACS) Gene and Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)The sacsin gene (SACS) is located on chromosome 13 (13q12.12: chr13:23,288,68923,433,763, GRCh38/hg38), with 145,075 bases, and is oriented in the minus strand of DNA
These findings suggest that, besides abnormal trafficking and cellular interactions, localizations could contribute to the reduced interaction between heat shock proteins and sacsin, leading to ARSACS pathology
Cells without functional sacsin showed a reduced degree of autophagosome aggregation and its fusion for lysosomes. These findings reveal that ARSACS dysfunctions could result in reduced clearance of damaged cellular organelles [36]

Summary

Introduction

The sacsin gene (SACS) is located on chromosome 13 (13q12.12: chr13:23,288,68923,433,763, GRCh38/hg38), with 145,075 bases, and is oriented in the minus strand of DNA Several cell and mouse models (hiPSC, SH-SY5Y, knockout mouse models) have been developed with high priority in ARSACS to reflect the accurate human conditions for the discovery of the disease mechanisms. SACS knockout mice, investigated by Larivière (2015), revealed typical ARSACS symptoms, loss of Purkinje cells in the cerebellum and abnormal aggregation on non-phosphorylated neurofilaments in the somatodendritic brain region with altered mitochondrial dynamics [12]. Human-induced pluripotent stem cells (hiPSC) were suggested to open new avenues in disease modeling and drug development They may mimic more correctly the disease mechanisms, even from the earliest cellular dysfunctions. Taken together, promising studies have been performed to analyze sacsin functions and ARSACS disease mechanisms in cell or mouse models, but further research is needed on the ideal disease model organism

Sacsin Protein Domains

SACS Genetics and Mutations

Potential Involvement of SACS in Other Neurodegenerative Diseases

ARSACS Diagnosis and Potential Therapeutics

Discussion and Future