Early-Onset Parkinson's Disease: Creating the Right Environment for a Genetic Disorder

Abstract

Parkinson's disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk.

Keywords: Parkinson’s disease; early-onset Parkinson’s disease; environment; genetics; risk factors.

Fig. 1

Environment and genetic interplay in EOPD. An interpretation of the multi-hit hypothesis on early-onset Parkinson’s disease suggests it is the combination of environmental agents acting on the background of genetic determinants that pre-disposes the individual to disease. Highlighted are both risk (pink-red or bold) and protective (green or italics) factors. This concept in early-onset forms of disease may be due to stronger effects sizes from exposure or higher penetrant genetic mutations observed in specific genes (e.g., SNCA or PRKN) and molecular pathways (e.g., mitophagy). (Created by BioRender.com)

Fig. 2

Mitophagy pathway. Two of the genes that have been identified to drive early-onset recessive forms of Parkinson’s disease have been demonstrated to play a major role in mitochondrial quality control measures of healthy mitochondria (A). The recessive loss of function for either the PINK1 or “PARKIN (PRKN)” proteins disrupts the normal mitochondrial surveillance process which induces the process of mitophagy for clearance of the damaged organelle (B). This dysfunction is believed to lead to the accumulation of damaged mitochondria eventually resulting in neuronal death. (Created by BioRender.com)

Fig. 3

GBA-mediated Lysosomal dysfunction. Mutations of the GBA gene that result in haploinsufficiency have been shown to result in loss of lysosomal homeostasis, a reduction of glucocerebrosidase activity, the build-up of lysosomal glucosylceramides and impairs α-synuclein degradation enhancing aggregation. (Created by BioRender.com)