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GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis
- Source :
- J Neurosci
- Publication Year :
- 2022
-
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 zebrafishgch1mutant (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 ofgch1–/–larvae improved survival without ameliorating the motor phenotype. RNAseq ofgch1–/–larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation ingch1–/–. 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.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 genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.
- Subjects :
- Tyrosine 3-Monooxygenase
DYSTONIA
Parkinson's disease
microglia
3124 Neurology and psychiatry
Animals, Genetically Modified
DOPAMINE
PARKINSONS-DISEASE
tyrosine hydroxylase
Animals
Homeostasis
GTP CYCLOHYDROLASE-I
Genetic Predisposition to Disease
GENOME-WIDE ASSOCIATION
GTP Cyclohydrolase
Research Articles
SUBSTANTIA-NIGRA
NITRIC-OXIDE
Sequence Analysis, RNA
Dopaminergic Neurons
General Neuroscience
3112 Neurosciences
Brain
Parkinson Disease
GTP cyclohydrolase 1
zebrafish
MICROGLIAL ACTIVATION
RISK LOCI
Immunity, Innate
MODEL
tetrahydrobiopterin
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J Neurosci
- Accession number :
- edsair.doi.dedup.....54bf4849624a19a851d58ffa5c648f3a