Uncoupling protein 2 haplotype does not affect human brain structure and function in a sample of community-dwelling older adults.

Verena Heise,Sana Suri,Nicola Filippini,Enikő Zsoldos,Mika Kivimäki,Anya Topiwala,Archana Singh-Manoux,Klaus P Ebmeier,Abda Mahmood,Claire Sexton,Clare E Mackay,Charlotte L Allan,Christos Papadelis

doi:10.1371/journal.pone.0181392

Abstract

Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that plays a role in uncoupling electron transport from adenosine triphosphate (ATP) formation. Polymorphisms of the UCP2 gene in humans affect protein expression and function and have been linked to survival into old age. Since UCP2 is expressed in several brain regions, we investigated in this study whether UCP2 polymorphisms might 1) affect occurrence of neurodegenerative or mental health disorders and 2) affect measures of brain structure and function. We used structural magnetic resonance imaging (MRI), diffusion-weighted MRI and resting-state functional MRI in the neuroimaging sub-study of the Whitehall II cohort. Data from 536 individuals aged 60 to 83 years were analyzed. No association of UCP2 polymorphisms with the occurrence of neurodegenerative disorders or grey and white matter structure or resting-state functional connectivity was observed. However, there was a significant effect on occurrence of mood disorders in men with the minor alleles of -866G>A (rs659366) and Ala55Val (rs660339)) being associated with increasing odds of lifetime occurrence of mood disorders in a dose dependent manner. This result was not accompanied by effects of UCP2 polymorphisms on brain structure and function, which might either indicate that the sample investigated here was too small and underpowered to find any significant effects, or that potential effects of UCP2 polymorphisms on the brain are too subtle to be picked up by any of the neuroimaging measures used.

Highlights

Uncoupling protein (UCP) 2 is a proton carrier found in the inner mitochondrial membrane
Due to the potential link between UCP2 gene variants, reactive oxygen species (ROS) production and longevity, we investigated in this study, whether UCP2 polymorphisms affect the risk of developing neurodegenerative diseases and whether they account for any variance in brain structure or function
The observed UCP genotype frequencies were in Hardy-Weinberg equilibrium (p = 0.62 for -866G>A and p = 0.57 for Ala55Val, Table 1) with values that are similar to those found in the 1000 genomes project (p = 0.59 for -866G>A and p = 0.58 for Ala55Val)

Summary

Introduction

Uncoupling protein (UCP) 2 is a proton carrier found in the inner mitochondrial membrane. There are few investigations of UCP2 expression in the human brain but expression has been shown in the cortex and basal ganglia with increased expression in the periphery of ischemic stroke lesions [3]. It affects neuronal function in multiple ways, e.g. as a regulator of production of reactive oxygen species (ROS) [4]. UCP2 overexpression in mice protects neurons in the substantia nigra of a Parkinson’s disease model [6]. UCP2 appears to play a role in neuronal plasticity and regeneration [7], and human UCP2 expression extends the lifespan of flies and mice [8]

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Results

Conclusion