In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Ataxin-2 (ATXN2) plays roles in stress responses, mRNA translation, and nutrient metabolism.
• ATXN2 knockout mice develop obesity and insulin resistance.
• Gain-of-function ATXN2 mutations cause spinocerebellar ataxia type 2 (SCA2), characterized by adipose tissue loss and muscle atrophy.

Purpose of the Study:

• To investigate lipid dysregulation in the brain of SCA2 patients.
• To analyze the lipid metabolome in a mouse model of ATXN2-related SCA2.
• To understand the molecular mechanisms underlying lipid anomalies in SCA2.

Main Methods:

• Lipidomic analysis using thin-layer chromatography on cerebellum from an SCA2 patient.
• Comparative lipidomic analysis of spinocerebellar tissue from Atxn2-CAG100-Knockin (KIN) mice.
• Spinocerebellar gene expression profiling in KIN mice.

Main Results:

• SCA2 patient cerebellum showed deficits in sulfatide, galactosylceramide, cholesterol, and specific sphingomyelins and gangliosides.
• KIN mice exhibited decreased ceramides and elevated sphingosine in cerebellum and spinal cord.
• Gene expression analysis revealed dysregulation of enzymes involved in ceramide-sphingosine metabolism and sphingomyelin synthesis.

Conclusions:

• A prominent deficit of myelin lipids occurs in SCA2 nervous tissue.
• Metabolic enzyme adaptations do not compensate for lipid deficits.
• Findings align with ATXN2's role in inhibiting mTORC1 signaling and promoting autophagy, impacting myelination.