The impact of genetic research on our understanding of Parkinson's disease

Abstract

Until recently, genetics was thought to play a minor role in the development of Parkinson's disease (PD). Over the last decade, a number of genes that definitively cause PD have been identified, which has led to the generation of disease models based on pathogenic gene variants that recapitulate many features of the disease. These genetic studies have provided novel insight into potential mechanisms underlying the aetiology of PD. This chapter will provide a profile of the genes conclusively linked to PD and will outline the mechanisms of PD pathogenesis implicated by genetic studies. Mitochondrial dysfunction, oxidative stress and impaired ubiquitin-proteasome system function are disease mechanisms that are particularly well supported by genetic studies and are therefore the focus of this chapter.

Figure 1. Timeline of key discoveries in PD pathogenesis

Parkinson’s disease was first formally described in 1817 by James Parkinson. From then until the late twentieth century, advances were made in describing the pathological features of PD and in understanding possible causes of the disease, such as exposure to pesticides and MPTP. The recent discovery of multiple genetic causes of PD has generated insight into novel mechanisms of PD etiology. Studies using genetic models of PD will, no doubt, continue to advance our understanding of disease pathogenesis.

Figure 2. Pathogenic mechanisms implicated by genetic studies of PD

This model links genetic mutations (autosomal recessive mutations in blue boxes and autosomal dominant mutations in purple boxes) to neurodegeneration via pathways involving mitochondrial dysfunction, oxidative stress and impaired ubiquitin-proteasome function. Loss-of-function mutations in PINK1 or Parkin cause PD possibly through a mechanism involving mitochondrial pathology and dysfunction. Deleterious effects of mitochondrial dysfunction include reduced ATP generation and oxidative stress due to elevated ROS generation. Loss of Parkin’s E3 ubiquitin ligase activity, may also lead to dopamine neuron toxicity via impaired ubiquitin-proteasome function and accumulation of Parkin’s substrates. Loss of DJ-1 antioxidant function may promote neuronal oxidative stress, as might reduced respiratory chain function and elevated intracellular calcium influx via pores created by α-synuclein oligomers. LRRK2 mutations might be linked to PD through altered protein translation further supporting a role for protein turnover in PD pathogenesis.