Mitochondrial quality control gene expression in peripheral blood mononuclear cells of SCA12 patients

Spinocerebellar ataxia type 12 (SCA12) is a late-onset, autosomal dominant neurodegenerative disorder linked to a CAG repeat expansion mutation in the PPP2R2B gene and prevalent in Indian Agarwal ancestry. The pathophysiology of SCA12 and its clinical relevance need further elucidation. Dysregulation of mitochondrial quality control (mitochondrial QC), a critical determinant of neurodegeneration, could play a central role in SCA12 pathogenesis.

In this study, 20 candidate genes regulating mitochondrial biogenesis, dynamics, mitophagy, mitochondrial transport, and protein folding were studied for their expression in SCA12 patient-derived peripheral blood mononuclear cells (PBMCs).

Twenty-four genetically confirmed SCA12 patients and healthy controls were recruited in the study. The patients were assessed for motor severity using the International Cooperative Ataxia Rating Scale (ICARS). PBMCs were isolated from the peripheral blood. Total RNA was extracted from the PBMCs, which were reverse transcribed to make cDNA. The relative mRNA expression was estimated using quantitative Real-time PCR.

Among the 20 candidate genes, a total of 5 genes, i.e., DNM1L, PPARGC1A, OPA1, NFE2L2, and BECN1, demonstrated a significantly reduced expression in SCA12 compared to healthy controls. There was no difference in the expression of other genes between groups.

This study suggests dysregulation of mitochondrial biogenesis, mitophagy, dynamics, and antioxidant system converging towards a compromised mitochondrial QC system in SCA12 patients.