GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis

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 gchl(-/-) larvae improved survival without ameliorating the motor phenotype. RNAseq of gchl(-/-) larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gchl(-/-). 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.

Automated summary

In this study, a loss of function zebrafish gch1(-/-) mutant was generated using CRISPR/Cas technology to investigate the mechanisms by which GCH1 deficiency may contribute to PD. The results suggest that GCH1 deficiency may indirectly contribute to neuronal cell death via immune-mediated mechanisms. The study highlights the importance of functional validation for GWAS risk factors and emphasizes the role of inflammation in the pathogenesis of PD.