Increased Burden of Rare Risk Variants Across Gene Expression Networks Predisposes to Sporadic Parkinson's Disease

Alpha-synuclein is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of alpha-synuclein in Parkinson's disease is unclear, it is thought that prionoid cell-to-cell propagation of alpha-synuclein has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates alpha-synuclein propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate alpha-synuclein homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) "3K" alpha-synuclein under doxycycline induction. 3K alpha-synuclein spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how alpha-synuclein interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson's disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson's disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of alpha-synuclein pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson's disease: increased burden of risk variants across genetic networks dysregulates pathways underlying alpha-synuclein homeostasis, thereby leading to pathology and neurodegeneration. ### Competing Interest Statement M.M.M. is an inventor of filed and issued patents related to α-synuclein. She is a founder of MentiNova, Inc.