Linking environmental risk factors with epigenetic mechanisms in Parkinson's disease

Abstract

Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease, with a complex risk structure thought to be influenced by interactions between genetic variants and environmental exposures, although the full aetiology is unknown. Environmental factors, including pesticides, have been reported to increase the risk of developing the disease. Growing evidence suggests epigenetic changes are key mechanisms by which these environmental factors act upon gene regulation, in disease-relevant cell types. We present a systematic review critically appraising and summarising the current body of evidence of the relationship between epigenetic mechanisms and environmental risk factors in PD to inform future research in this area. Epigenetic studies of relevant environmental risk factors in animal and cell models have yielded promising results, however, research in humans is just emerging. While published studies in humans are currently relatively limited, the importance of the field for the elucidation of molecular mechanisms of pathogenesis opens clear and promising avenues for the future of PD research. Carefully designed epidemiological studies carried out in PD patients hold great potential to uncover disease-relevant gene regulatory mechanisms. Therefore, to advance this burgeoning field, we recommend broadening the scope of investigations to include more environmental exposures, increasing sample sizes, focusing on disease-relevant cell types, and recruiting more diverse cohorts.

Fig. 1

Exposures and environmental risk factors reported to be associated with Parkinson’s disease.

Fig. 2. Overview of reported links between environmental risk factors of PD and epigenetic mechanisms.

The pesticide paraquat upregulates α-syn and facilitates colocalisation with histones in mouse nigral neurons. Paraquat also increases acetylation of multiple histone residues in SH-SY5Y cells and rat N27 dopaminergic cells, the latter via inhibition of HDAC. MPP⁺ (indicated in brackets as it is not strictly an environmental exposure) and rotenone increase acetylation of histones in SH-SY5Y cells, while dieldrin has the same effect in N27 cells as well as SNpc and striatum of mice. The heavy metal manganese increases methylation of CpG sites in SH-SY5Y cells. In human PD cases and SNCA transgenic mice, α-syn sequesters DNMT1 out of the nucleus, thereby reducing total levels of DNA methylation^,–,.

Fig. 3

PRISMA flow diagram of study selection.