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

J Parkinsons Dis. 2022;12(8):2353-2367. doi: 10.3233/JPD-223380.


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Middle Aged
  • Mitochondria / pathology
  • Movement
  • Mutation
  • Parkinson Disease*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • alpha-Synuclein
  • Ubiquitin-Protein Ligases