PAK1 expression protects cellular and behavioral defects in animal models of Parkinson' s disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Although various therapeutics have been developed, no disease-modifying treatment has been established to date. Recent studies highlight critical roles of p21-activated protein kinases (PAKs) in the pathogenesis of PD. To investigate the potential of PAK1 as a therapeutic target for PD, we examined the effects of a constitutively active form of PAK1 (PAK1-T423E; PAK1-CA) in animal models. An animal model of PD, recapitulating α-synucleinopathy was established by injecting human α-synuclein preformed fibrils into the biceps femoris of M83 A53T homozygous mice. PAK1-CA expression significantly ameliorated behavioral deficits and prevented the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Moreover, PAK1-CA expression increased the survival rate, although it was not significant in this model. In contrast, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxin model, PAK1-CA expression significantly improved survival rates compared to the GFP-expressing control group. These findings suggest a potential role for constitutively active PAK1 in contributing to the neuroprotection of dopaminergic neurons, which may imply its utility as a candidate for gene therapy.