Monogenic forms of Early-onset Parkinson’s (EOPD) allow us to connect genetic lesions to biological processes that culminate in the loss of midbrain dopaminergic (DA) neurons to cause motor symptoms of PD. Rare but highly penetrant mutations in the E3 ubiquitin ligase, Parkin, and the ubiquitin kinase, PINK1, lead to autosomal-recessive juvenile onset Parkinson’s. PINK1 and Parkin act to eliminate damaged mitochondria via selective autophagic turnover i.e., PINK-Parkin mitophagy. Mitochondria that encounter depolarisation stress induced by Complex I inhibitors are selectively removed via PINK1-Parkin mitophagy. Interestingly, mitochondrial Complex I inhibitors (e.g. paraquat, rotenone and MPP+) selectively induce the loss of dopaminergic neurons in humans and mice leading to parkinsonism. Thus, studying Complex I subunits in Parkin PD brains may provide insights into how genetics can impact susceptibility to environmental toxins associated with PD.
We established 3 EOPD mouse models of Parkin dysregulation, i.e. Parkin deletion (delATG) and mice harbouring Parkin patient mutations (K161N and R275W). We then biochemically validated mitophagy deficits in midbrain DA neurons derived from these animals. Further, we measured changes in total proteome and ubiquitylated proteome (ubiquitylome) in the midbrains of these mice. Strikingly, we found alterations in mitochondrial Complex I components as a common signature in both Parkin patient mutation mouse models suggesting a potential heightened dependence or compensatory changes in this important component of mitochondrial electron transport. These data provide new insights into the pathogenesis of PD due to loss of Parkin function.