The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis
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, includ...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/164554 |
| _version_ | 1826128710415155200 |
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| author | 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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 |
| author_sort | Zhou, Zhi Dong |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:29:24Z |
| format | Journal Article |
| id | ntu-10356/164554 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:29:24Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1645542023-03-05T16:54:33Z The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis 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 Lee Kong Chian School of Medicine (LKCMedicine) National Neuroscience Institute Science::Medicine Dopamine Neurodegeneration 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. Published version This study was supported by Singapore National Medical Research Council (NMRC), STaR 0030/2018 and OF PD LCG 000207 to T-EK. 2023-02-01T01:23:30Z 2023-02-01T01:23:30Z 2022 Journal Article 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-. https://dx.doi.org/10.1007/s00018-022-04574-x 1420-682X https://hdl.handle.net/10356/164554 10.1007/s00018-022-04574-x 36409355 2-s2.0-85142279241 12 79 599 en Cellular and Molecular Life Sciences © 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 http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Medicine Dopamine Neurodegeneration 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 The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title | The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title_full | The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title_fullStr | The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title_full_unstemmed | The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title_short | The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis |
| title_sort | role of tyrosine hydroxylase dopamine pathway in parkinson s disease pathogenesis |
| topic | Science::Medicine Dopamine Neurodegeneration |
| url | https://hdl.handle.net/10356/164554 |
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