Targeting Cdc42 improves motor phenotype in Parkinson's disease mice and reveals age-dependent susceptibility to α-synuclein.

ABSTRACT: Aging and accumulation of α-synuclein (α-syn) oligomers in the brain are indisputably linked to Parkinson's disease (PD). Using an inducible α-syn oligomer mouse model, we demonstrate that the induction of PD-associated α-syn oligomers for the same time span caused PD-associated symptoms only in aged, but not in young mice. Biochemical studies revealed that α-syn oligomer formation precedes motor decline, with age and α-syn expression jointly determining the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD-related transcriptional signature in basal ganglia neurons (BGNs), which overlapped in part with aging-associated changes. Short-term pharmacological inhibition of the small RhoGTPase CDC42 in aged, symptomatic animals improved motor function without reducing ol

SUBMITTER: Bopp V 

PROVIDER: S-EPMC12744266 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature