Elsevier

Neurobiology of Aging

Volume 50, February 2017, Pages 39-46
Neurobiology of Aging

Regular article
Aging modifies the effect of GCH1 RS11158026 on DAT uptake and Parkinson's disease clinical severity

https://doi.org/10.1016/j.neurobiolaging.2016.10.006Get rights and content

Abstract

Novel single nucleotide polymorphisms within Parkinson's disease (PD) can predict disease risk, but their influence on clinical, cognitive, and neurobiological indices remains unexplored. We investigated differences between functional polymorphisms at RS11158026 coding for guanosine triphosphate cyclohydrolase-1 (GCH1), an essential enzyme for dopamine production in nigrostriatal cells. Among newly diagnosed, untreated PD subjects and age-matched controls from the Parkinson's Progression Markers Initiative, T allele carriers showed higher PD risk (odds ratio = 1.23, p = 0.048), earlier age of onset by 5 years (p = 0.003), and lower striatal dopamine reuptake transporter uptake (p = 0.003). Carriers also had increased cerebrospinal fluid α-synuclein (p = 0.016), worse motor function (p = 0.041), anxiety (p = 0.038), and executive function (p < 0.001). Strikingly, these effects were only in younger T carriers (<50 years), where aging quells the effects of these genetic factors. This suggests GCH1 variants affect early PD risk through altered dopamine uptake, and aging alters how genetic factors contribute to disease development. Future studies should investigate how aging modifies genotypes' contributions on PD risk and sequelae.

Introduction

Parkinson's disease (PD) is an age-related disorder resulting from degeneration of nigrostriatal dopaminergic neurons. PD is believed to be due to α-synuclein aggregation (Allen Reish and Standaert, 2015), decreasing dopamine production whereby many genetic risk factors act individually or in concert to impact disease pathogenesis (Lesage and Brice, 2009). Guanosine triphosphate cyclohydrolase-1 (GCH1; OMIM 600225), located on chromosome 14q22.1-q22.2, encodes the rate-limiting enzyme catalyzing the first step in tetrahydrobiopterin (BH4) synthesis. BH4 is a required cofactor for tyrosine hydroxylase, ultimately leading downstream to production of dopamine (Kurian et al., 2011).

Recently, a large-scale meta-analysis of genome-wide association study data identified new risk loci for the development of PD (Nalls et al., 2014), including a novel variant at RS11158026, hereafter RS026, for GCH1. No studies have investigated how RS026 variants affect clinical characteristics in PD in populations of European descent. Furthermore, it is unknown how the RS026 T or C alleles may impact neural, cognitive, or biomarker sequelae relevant to PD or dopamine transport uptake, such as α-synuclein(Goedert, 2001), tau species (Kang et al., 2016), as well as metabolic factors like cholesterol that may affect dopamine uptake(Jones et al., 2012).

This study explored relationships between markers of PD with a GCH1 mutation, to determine if mutation carriers of European origin are at increased risk of developing PD. We describe the clinical, neuropsychological, volumetric imaging, and dopaminergic imaging findings of GCH1 variants in a cross-sectional cohort of newly diagnosed, untreated individuals with PD and healthy, age-matched controls. We also wished to explore how RS026 impacted processes among young and older subjects, as aging is the greatest PD risk factor (Rodriguez et al., 2015) and may impact the effect of RS026.

Section snippets

Setting

The Parkinson's Progression Markers Initiative (PPMI) is described at www.ppmi-info.org. PPMI is a public–private partnership funded by the Michael J Fox Foundation for Parkinson's Research and funding partners listed at www.ppmi-info.org/fundingpartners. PPMI is an observational, multicenter longitudinal case-control study designed to identify PD biomarkers (The Lancet Neurology, 2010).

Participants

PPMI data was obtained from 189 de novo PD and 133 aged healthy controls, including (1) demographic data; (2)

Data summary

Clinical, demographic, and CSF data are presented in Table 1. There were no differences between genotypes in BMI, years of education, age at baseline, or the percentage of individuals diagnosed with PD. The 2 subjects with the youngest age of PD diagnosis (16 and 24) both were carriers for a T allele. We did not observe any significant difference in genotype distribution between PD patients and controls even after stratifying by early PD onset (<50 years) versus late PD (>50). As expected,

Discussion

Several studies examining dopamine dysregulation in PD and DRD (Lewthwaite et al., 2015, Mencacci et al., 2014) suggest GCH1 deficiency may contribute to the pathologic features of PD through dopamine deficiency. This is the first study to assess whether GCH1 variants explained PD age of onset, striatal DAT uptake, and both clinical and cognitive markers of PD. Our main findings include a gene-dose response of the minor allele contributing to an earlier age of onset, markedly lower DAT uptake,

Conclusion

This is the first study to demonstrate a significant association of GCH1 RS026 with factors of PD in a European population, whose results would contribute significantly to the future meta-analyses evaluating PD development using genetic loci. Overall, this PPMI data suggest that GHC1 functional variants represent rare variant risk factors for clinical PD that whose effects are significantly affected by aging. Given GCH1's reported function in BH4 and dopamine synthesis, it is likely for GCH1

Disclosure statement

The authors have no actual or potential conflicts of interest.

Acknowledgements

This study was funded by Iowa State University and NIH AG047282. Neither funding source had any involvement in the report. Data used in the preparation of this article were obtained from the Parkinsons Progression Markers Initiative database (www.ppmi-info.org/data), a public–private partnership funded by the Michael J. Fox Foundation for Parkinsons Research and funding partners, including Abbott, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, lan, GE Healthcare,

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