In an MPTP-induced mouse model of Parkinson's, local Serping1 siRNA delivery preserved motor function and tyrosine hydroxylase levels in the substantia nigra and striatum while reducing pSer129-α-synuclein and inflammatory markers (COX-2, iNOS).

Positions SERPING1 as a modifiable inflammatory/complement-related target that reduces α-syn pathology and neurodegeneration in vivo, offering actionable therapeutic and repurposing opportunities (but requiring validation of delivery, mechanism, and safety).

Background: Decreased dopaminergic cells and tyrosine hydroxylase (TH) in the substantia nigra (SN) lead to Parkinson's disease (PD); but its cause remains unknown. PD is characterized by α-synuclein (α-syn) accumulation in Lewy bodies; most of which is phosphorylated at Ser129 (pSer129 α-syn). Serping1 is an important gene for controlling blood vessel maintenance; including the process of inflammation. Methods: Increased expression of Serping1 affects dopaminergic cell death in the SN of a chronic PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); and Serping1 siRNA treatment has a therapeutic effect in this model. Results: We demonstrated that this treatment shows a normal status in the motor ability test and TH level in the SN and striatum. Serping1 siRNA was found to react to decreased Serping1 levels in the SN. In the pSer129-α-syn level of the SN region; Serping1 siRNA had a greater positive effect on PD than N-acetylcysteine by inhibiting pSer129-α-syn formation. Cyclooxygenase-2 and inducible nitric oxide synthase levels were decreased by Serping1 siRNA treatment; thereby indicating its effect on inflammation. Conclusions: Our findings suggest that Serping1 siRNA may represent a potential therapeutic approach for PD; warranting further investigation.