Figure 6.

The degeneration of dopaminergic neurons in Parkinson’s disease involves impaired ETC function, proteasomal overload and excitotoxicity. Mitochondrial complex I activity is reduced in vulnerable neurons in PD, likely as the result of a combination of normal aging, exposures to environmental toxins and genetic factors. The resulting ATP depletion and increased levels of ROS render neurons vulnerable to excitotoxic Ca²⁺ overload. Mutations in genes that cause inherited PD (α-synuclein, Parkin, DJ-1, PINK1, UCHL1 and LRRK2) may adversely affect mitochondrial function either indirectly or directly. Mutations of α-synuclein (or increased amounts of wild-type α-synuclein caused by increased expression or decreased proteasomal degradation) results in the formation of α-synuclein oligomers which may exacerbate ROS-mediated damage to mitochondrial membranes and proteins. UCHL2 mutations may contribute to proteasomal overload in PD. Parkin is a ubiquitin E3 ligase that plays important roles in removing damaged proteins from neurons; this E3 ligase activity is reduced in PD resulting in excessive accumulation of damaged/neurotoxic proteins. Parkin may affect one or more proteins of the PTP, thereby preventing cytochrome c release and apoptosis. DJ-1 is a mitochondrial protein that reduces ROS and blocks PTP formation. PINK1 is important for the maintenance of membrane potential and suppression of oxidative stress. Thus, mutations in DJ-1 and PINK1 promote damage to mitochondria. E1, ubiquitin E1 ligase; E2, ubiquitin E2 ligase; LRRK2, leucine-rich repeat kinase 2; UCHL1, ubiquitin C-terminal hydrolase L1.