Please use this identifier to cite or link to this item:
Title: The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis
Authors: Zhou, Zhi Dong
Saw, Wuan Ting
Ho, Patrick Ghim Hoe
Zhang, Zhi Wei
Zeng, Li
Chang, Ya Yin
Sun, Alfred Xu Yang
Ma, Dong Rui
Wang, Hong Yan
Zhou, Lei
Lim, Kah-Leong
Tan, Eng-King
Keywords: Science::Medicine
Issue Date: 2022
Source: Zhou, Z. D., Saw, W. T., Ho, P. G. H., Zhang, Z. W., Zeng, L., Chang, Y. Y., Sun, A. X. Y., Ma, D. R., Wang, H. Y., Zhou, L., Lim, K. & Tan, E. (2022). The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis. Cellular and Molecular Life Sciences, 79(12), 599-.
Journal: Cellular and Molecular Life Sciences 
Abstract: Background: Parkinson’s disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. Methods: We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)–DA pathway. Results: We demonstrated that PD-linked LRRK2 mutations were able to modulate TH–DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH–DA pathway. Conclusions: Our findings highlight the vital role of the TH–DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH–DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH–DA pathway inhibitors in early or prodromic PD.
ISSN: 1420-682X
DOI: 10.1007/s00018-022-04574-x
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: National Neuroscience Institute
Rights: © 2022 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

Files in This Item:
File Description SizeFormat 
s00018-022-04574-x.pdf6.75 MBAdobe PDFThumbnail

Citations 50

Updated on Dec 5, 2023

Web of ScienceTM
Citations 50

Updated on Oct 28, 2023

Page view(s)

Updated on Dec 10, 2023


Updated on Dec 10, 2023

Google ScholarTM




Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.