Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson’s Disease Influence Sporadic Forms?

Abstract

Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD.

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

“…The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, and the post-translational modification of histones and non-coding RNAs (ncRNAs, the most studied of which are microRNAs or miRNAs). The regulation of genes responsible for monogenic forms of PD may also be involved in sporadic PD [ 19 ].…”

Epigenetic Interface of Autism Spectrum Disorders (ASDs): Implications of Chromosome 15q11–q13 Segment

“…Recent studies have shown that methylation of the SNCA gene (the gene coding for α-synuclein) may be involved in disease via structural changes or overexpression of the protein, leading to protein aggregation, or via impaired gene expression. 4 It is reported that there is a reduced SNCA gene methylation in the substantia nigra in patients with PD as well as PARK16/Iq32, GPNMB aberrant gene methylation in PD patients postmortem. The current knowledge of various epigenetic mechanisms and their role in regulation of transcriptional and translational machinery have hinted toward a vast arena that still needs to be explored to completely understand the processes involved in neurodevelopment as well as manifestation of neurodevelopmental disorders.…”

“…Further, most of the studies evaluating the role of epigenetics in pathogenesis have focused on the analysis of promoter methylation of causative Parkinson’s disease (PD) genes in post-mortem brains and peripheral blood. Recent studies have shown that methylation of the SNCA gene (the gene coding for α-synuclein) may be involved in disease via structural changes or overexpression of the protein, leading to protein aggregation, or via impaired gene expression . It is reported that there is a reduced SNCA gene methylation in the substantia nigra in patients with PD as well as PARK16/Iq32, GPNMB aberrant gene methylation in PD patients post-mortem.…”

Special Issue “Parkinson’s Disease: Genetics and Pathogenesis”

“…The regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. Lanoré et al [ 9 ] reviewed the epigenetic mechanisms regulating gene expression, including DNA methylation, histone modification and epigenetic changes by non-coding RNAs. An example is SNCA , encoding α-Synuclein, with the understanding of its regulation being a longstanding central focus for the community working on PD.…”