Neuronal titration of <i>Snca</i> via enhancer disruption mitigates disease onset in a Parkinson's disease mouse model.

ABSTRACT: α-synuclein (SNCA) is the greatest genetic risk factor for sporadic Parkinson's Disease (PD). Misfolding and overexpression of SNCA underlie pathognomonic features of PD, including SNCA aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbors variation associated with PD risk and demonstrated its role as a neuronal cis-regulatory element (CRE). Here, we engineered a mouse model lacking this sequence, which exhibits significantly reduced Snca transcription in mbDA neurons. Employing a battery of motor, molecular, and histological assays in an established mouse model of PD, we demonstrate that mice lacking this Snca enhancer are protected against PD-relevant histopathology and motor impairments. B

SUBMITTER: Boyd RJ 

PROVIDER: S-EPMC12047861 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature