Abnormal Amyloidogenesis Identified in Plasma of Patients with Spinocerebellar Ataxia Type 12

Spinocerebellar ataxia type 12 (SCA12), a progressive neurological disorder, is the second-most common autosomal dominant ataxia in India. The disease is clinically heterogeneous with a variable age-of-onset. A CAG repeat expansion mutation upstream of PPP2R2B gene is causal to SCA12 motor and non-motor symptoms but its pathophysiological significance remains unknown. PPP2R2B encodes for the regulatory subunit B of the protein phosphatase 2 A (PP2A), a major regulator of amyloid beta (Aβ) and tau proteins. We aimed to determine whether PPP2R2B mutation leads to Aβ and tau dysregulation in SCA12. Plasma Aβ42/Aβ40 ratio, a core biomarker for Aβ toxicity and cognitive impairment was further investigated. This cross-sectional study included 27 genetically confirmed SCA12 patients and 24 healthy controls. The patients were subjected to ICARS and MoCA clinical scales for disease severity and cognition respectively. Plasma levels for Aβ42, Aβ40, total tau (t-tau) and phosphorylated tau (p-tau) levels were estimated spectrophotometrically using validated ELISA kits. A significant decrease in the plasma Aβ40 level (p = 0.014) and an increase in the Aβ42/Aβ40 ratio (p = 0.007) was observed in SCA12. Total tau and p-tau levels were unchanged. No significant correlation of the plasma Aβ and tau proteins with clinical parameters was obtained. In SCA12, we identified an altered plasma Aβ profile indicative of abnormal peripheral amyloidogenesis. Plasma Aβ and tau concentrations were not correlated with the patients' cognitive status. The dynamic ratiometric Aβ42/Aβ40 shift in plasma is a forerunner of Aβ neurotoxicity and opens novel avenues for Aβ-targeted therapy in SCA12.