Multi-omics comparative analyses of synucleinopathy models reveal distinct drug targets and relevance for drug development

Abstract

Understanding how preclinical models of Parkinson’s disease (PD) reflect mechanisms underlying PD is crucial for successful drug development. To illuminate the translational value of two well-established rat synucleinopathy models – substantia nigral AAV-delivered human mutant α-Synuclein (α-Syn-hA53T) and striatal α-Syn preformed fibril (PFF)-injection – unbiased transcriptomic and proteomic analyses were employed and the genes, proteins, and pathways disrupted in striatum and substantia nigra were assessed. Unbiased analyses identified 388 proteins altered in hA53T-α-Syn and 1550 in PFF-α-Syn compared to control brain. Pathway and correlation analyses of the altered proteins revealed distinct processes impacted in each model: Dopaminergic signaling/metabolism, mitochondria and energy metabolism, and motor processes were most predominately disrupted in the AAV-hA53T-α-Syn model, whereas immune response, intracellular/secretory and synaptic vesicles, and autophagy were predominately disrupted in PFF-α-Syn model. Both models reflected aberrant synaptic function, neural growth/remodeling, and protein localization. The set of disrupted proteins/genes were compared to that aberrantly expressed in human PD and dementia with Lewy bodies (DLB) and candidate drug targets in a “PD drug development pipeline”, revealing potential disease biomarkers and optimal models for testing novel therapeutics. Not applicable.