Serum UCHL-1, GFAP, and NfL track tyrosine hydroxylase loss in substantia nigra in two Rat Models of Parkinson’s Disease

In Parkinson's disease (PD), blood-based (BB) biomarkers ubiquitin c-terminal hydrolase L 1 (UCHL-1), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) correlate with motor or cognitive impairment. However, it is unclear if blood levels of these biomarkers represent changes in nigrostriatal neuron viability or dopamine (DA) signaling. In 6-OHDA and Pink1 knockout (KO) rat models that showed progressive loss of DA tissue and tyrosine hydroxylase (TH) protein, we quantified UCHL-1, GFAP, and NfL expression in striatum and substantia nigra (SN) at 7- and 28-days in the 6-OHDA model and 7- and 18-month old in Pink 1 KO. Substantial changes in all biomarkers occurred with TH loss in SN, but not striatum, in both models. UCHL-1 levels increased against remaining TH protein. Accordingly, serum UCHL-1 levels increased 25% at 28 days post-6-OHDA and 18-month old Pink1 KO. GFAP and NfL levels increased in SN 28 days post-6-OHDA and 18 month-old Pink1 KO. Serum GFAP levels increased 28 days post-6-OHDA and 18 month-old Pink1 KO. Serum levels of NfL increased 28 days post-6-OHDA, and in 18 month-old Pink1 KO and wild-type, without influence by genotype. Expression levels of each biomarker were greater in the SN vs striatum, suggesting the SN contributes greater quantities of biomarkers to the blood and reflect TH loss therein. Taken together, our preclinical results show alignment between serum levels of UCHL-1, GFAP, and NfL and loss of TH and DA in the SN. As such, these biomarkers may be relevant peripheral indicators of deficient nigrostriatal DA signaling, and reflect nigrostriatal function in PD.