Genetic co-regulation of neopterin and Parkinson’s disease

TL;DR

Neopterin levels are genetically linked to Parkinson's disease through the GCH1 gene, suggesting a potential new target for understanding and treating the disease.

Contribution

The study identifies genetic signals in GCH1 associated with neopterin and Parkinson’s disease, revealing a potential mechanism involving GCH1 isoforms and dopamine metabolism.

Findings

Neopterin levels rise with aging and correlate with neurodegeneration and inflammation markers.

Two genetic signals in GCH1 are associated with neopterin levels and Parkinson’s disease risk.

A shorter, inactive GCH1 isoform is linked to Parkinson’s disease predisposition and reduced GCH1 stability.

Abstract

Neopterin is a pro-inflammatory molecule upregulated in several diseases; however, its role in pathophysiology is unclear and its genetic regulation is unexplored. We observed that neopterin levels increase during senescence (P-value = 1.88×10-13, beta = 0.96) and positively correlate with age-related neurodegeneration and inflammation markers. The heritability estimation of neopterin variation was 35%. We then conducted a genome-wide association study on 999 Sardinians, identifying two signals in the GTP cyclohydrolase (GCH1) gene that were suggestively associated with neopterin levels. The first signal, led by rs140884539-C (P-value = 7.05×10-08, beta = 0.59), was in strong linkage disequilibrium with variants associated with predisposition to rheumatoid arthritis, decrease in dopamine, increased levels of GCH1 transcript, dopamine metabolites, and galectin-3. The second signal, represented by rs12323905-T (P-value = 8.17×10-08, beta = 0.30), colocalised with GCH1 splicing and Parkinson’s disease signals. Transcriptome analysis of 605 Sardinians showed that the Parkinson’s disease-predisposing variant was significantly associated with an increase in a shorter and inactive form of GCH1, whose presence is predicted to reduce the GCH1 decamer stability. The GCH1 homo-decamer regulates neopterin and tetrahydrobiopterin production, a cofactor required for the synthesis of dopamine and serotonin. Our data motivate experimental work to test whether modulating GCH1 expression or isoform ratio alters dopaminergic function in Parkinson’s disease models.

Figures