Zhou Zhi Dong, MD & PhD | National Neuroscience Institute of Singapore Pte Ltd; Alfred Sun Xu Yang, PhD | Duke-NUS; Eng King Tan, MBBS, MRCP (United Kingdom), FAMS (Neurology), FRCP (Edinburgh), NNI
Competition Sponsor: Ministry of Health and National Research Foundation of Singapore
Awardee year: 2024
Parkinson’s disease (PD) is the second most common age-dependent neurodegenerative disease with progressive dopamine (DA) neurodegeneration in PD brains. PD results in high rates of disability and need for care, especially for elderly. α-synuclein (α-syn) is an established PD biomarker and therapeutic target. The α-syn protein is prone to form deleterious protein aggregates and is the primary structural component of Lewy bodies in PD patient brains, including sporadic and familial forms of PD. In preliminary study, we have shown that the neurotoxicity of wild type (WT) and mutant α-syn to DA neurons can be endogenous DA dependent and inhibition of Tyrosine hydroxylase (TH) by α-methyl-L-tyrosine (α-MT), a clinical grade competitive and reversible TH inhibitor, can rescue α-syn induced neurodegeneration of DA cells. α-MT is an orally TH inhibitor used for multiple human disorders, including hypertension-linked phaeochromocytoma and Dystonia, Dyskinesia and Huntington’s disease. The low dose α-MT treatment on human subjects has been shown to be safe with insignificant side effects even after prolonged time usage. Application of α-MT can protect against LRRK2 mutations and other PD factors induced DA neurodegeneration. We propose to test and validate whether early-stage application of TH inhibitor α-MT can protect DA neurons against WT and mutant α-syn induced DA neurodegeneration in our transgenic Drosophila and human midbrain organoid PD models. Successful execution of the current study and achievements from this project will help pave the way for future application of TH inhibition as a new therapeutic strategy against DA neurodegeneration in PD.