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

Parkinson's disease (PD) is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body (LB) aggregates, neuronal loss, and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic PD. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of PD, including insoluble LB 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). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils (PFF) was used to seed PD pathology (or PBS vehicle) in these mice. Cohorts of mice harboring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, LB acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn PFF, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against PD-relevant histopathology, including DA neurodegeneration, LB acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduce the onset, severity and progression of PD pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for PD.