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. Author manuscript; available in PMC: 2015 Jun 2.
Published in final edited form as: Prog Brain Res. 2010;183:21–41. doi: 10.1016/S0079-6123(10)83002-X

Figure 2. Pathogenic mechanisms implicated by genetic studies of PD.

Figure 2

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.