PUBLICATION
GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis
- Authors
- Larbalestier, H., Keatinge, M., Watson, L., White, E., Gowda, S., Wei, W., Koler, K., Semenova, S.A., Elkin, A.M., Rimmer, N., Sweeney, S.T., Mazzolini, J., Sieger, D., Hide, W., McDearmid, J., Panula, P., MacDonald, R.B., Bandmann, O.
- ID
- ZDB-PUB-211211-8
- Date
- 2021
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 42(4): 702-716 (Journal)
- Registered Authors
- Bandmann, Oliver, Keatinge, Marcus, Semenova, Svetlana, Sieger, Dirk
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Brain/enzymology*
- Brain/immunology
- Dopaminergic Neurons/enzymology
- Dopaminergic Neurons/immunology
- GTP Cyclohydrolase/deficiency*
- GTP Cyclohydrolase/genetics
- Genetic Predisposition to Disease/genetics
- Homeostasis/physiology*
- Immunity, Innate/physiology*
- Parkinson Disease/enzymology
- Parkinson Disease/genetics
- Parkinson Disease/immunology
- Sequence Analysis, RNA/methods
- Tyrosine 3-Monooxygenase/antagonists & inhibitors
- Tyrosine 3-Monooxygenase/genetics
- Tyrosine 3-Monooxygenase/metabolism*
- Zebrafish
- PubMed
- 34876467 Full text @ J. Neurosci.
Citation
Larbalestier, H., Keatinge, M., Watson, L., White, E., Gowda, S., Wei, W., Koler, K., Semenova, S.A., Elkin, A.M., Rimmer, N., Sweeney, S.T., Mazzolini, J., Sieger, D., Hide, W., McDearmid, J., Panula, P., MacDonald, R.B., Bandmann, O. (2021) GCH1 deficiency activates brain innate immune response and impairs tyrosine hydroxylase homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 42(4):702-716.
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.SIGNIFICANCE STATEMENTGenome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of GWAS risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase I (GCH1) as a genetic risk factor for PD was counterintuitive - GCH1 is the rate-limiting enzyme in the synthesis of dopamine, mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing dopaminergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping