Genetic risk factors in Parkinson’s disease

Abstract

Over the last two decades, we have witnessed a revolution in the field of Parkinson’s disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

“…However, it is suggested that PD has a complex etiology, involving several molecular pathways, and understanding these specific pathways will be key to establishing mechanistic targets for therapeutic intervention. While several key pathways are currently being investigated, including autophagy, endocytosis, immune response and lysosomal function, [4][5][6][7] mitochondrial function was the first biological process to be associated with PD 8,9 .…”

The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

“…The etiology of PD is complex, including genetic, epigenetic, and environmental factors. Familial PD accounts for less than 10% of the total cases, mostly attributed to monogenic forms with autosomal‐dominant (including SNCA , LRRK2 , and VPS35 ) or autosomal‐recessive pattern of inheritance, such as PARKIN , PINK1 , and DJ‐1 , among others . However, the vast majority of the disease is considered to be sporadic, likely caused by the cumulative effect of multiple common or rare variants of small or moderate effect sizes in addition to other unknown environmental and stochastic factors.…”

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

“…The severity of disease correlates with the progressive spread of aggregated αSyn in patients 3 , and αSyn misfolding is associated with toxicity in cell and animal models 4 . In addition, strong genetic evidence links αSyn to PD including gene multiplications or missense mutations that cause rare early onset forms of PD [5][6][7] and genetic association studies also link αSyn to sporadic PD 8,9 . This combined neuropathological, biochemical and genetic evidence provides strong support implicating the misfolding and aggregation of αSyn as a key feature in PD.…”