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.
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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 |
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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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