# 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.

## Key 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.