Work

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

Year: 2026

Type: article

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.

Source: Discover Neuroscience

DOI: 10.1186/s13064-026-00321-1