4.7 Article

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

期刊

JOURNAL OF NEUROSCIENCE
卷 42, 期 4, 页码 702-716

出版社

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0653-21.2021

关键词

Parkinson's disease; GTP cyclohydrolase 1; tetrahydrobiopterin; zebrafish; tyrosine hydroxylase; microglia

资金

  1. Parkinson's UK [G1404, G1704]
  2. Medical Research Council (MRC) [MR/R011354/1, MR/M006646/1]
  3. National Institute for Health Research Sheffield Biomedical Research Center (BRC)
  4. Biotechnology and Biological Sciences Research Council (BBSRC) [BB/S010386/1]
  5. BBSRC [BB/M002322/1]
  6. Wellcome Trust [105624]
  7. Protein Production Laboratory at the Technology Facility, Department of Biology, University of York, United Kingdom
  8. BBSRC [BB/M002322/1, BB/S010386/1] Funding Source: UKRI
  9. MRC [MR/R011354/1] Funding Source: UKRI

向作者/读者索取更多资源

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.
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.

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