Larbalestier, H., Keatinge, M., Watson, L. et al. (15 more authors) (2022) GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis. The Journal of Neuroscience, 42 (4). pp. 702-716. ISSN 0270-6474
Abstract
The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1–/–), using CRISPR/Cas technology. gch1–/– zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1–/– larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1–/– larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1–/–. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Author(s). Reproduced in accordance with the publisher's self-archiving policy. This article is distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | GTP cyclohydrolase 1; Parkinson's disease; microglia; tetrahydrobiopterin; tyrosine hydroxylase; zebrafish; Animals; Animals, Genetically Modified; Brain; Dopaminergic Neurons; GTP Cyclohydrolase; Genetic Predisposition to Disease; Homeostasis; Immunity, Innate; Parkinson Disease; Sequence Analysis, RNA; Tyrosine 3-Monooxygenase; Zebrafish |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/R011354/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Feb 2023 10:52 |
Last Modified: | 28 Feb 2023 10:52 |
Status: | Published |
Publisher: | Society for Neuroscience |
Refereed: | Yes |
Identification Number: | 10.1523/jneurosci.0653-21.2021 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196863 |
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