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GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis

Larbalestier, H; Keatinge, M; Watson, L; White, E; Gowda, S; Wei, W; Koler, K; ... Bandmann, O; + view all (2022) GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis. Journal of Neuroscience , 42 (4) pp. 702-716. 10.1523/JNEUROSCI.0653-21.2021. Green open access

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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 dpf, movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase 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 morphological 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 GWAS risk factors and further emphasises the important role of inflammation in the pathogenesis of PD.

Type: Article
Title: GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.0653-21.2021
Publisher version: https://doi.org/10.1523/JNEUROSCI.0653-21.2021
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Parkinson’s disease; GTP cyclohydrolase 1; tetrahydrobiopterin; zebrafish; tyrosine hydroxylase; microglia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10140799
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