Selective vulnerability of dopaminergic neurons in Parkinson's disease connects PRKN and differential expression of CHCHD2 and GPNMB.

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The mechanism(s) causing selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) remain largely elusive. To improve our understanding of mitochondrial involvement and related pathways suggested to play a role in this selective vulnerability, we used tyrosine hydroxylase (TH)-mCherry reporter-induced pluripotent stem cells generated by CRISPR/Cas9. We sorted neurons into pure TH-positive and TH-negative neurons upon differentiation into a dopaminergic neuron-containing cell culture. We characterized mitochondrial function in both dopaminergic and non-dopaminergic neurons from PD patients and controls and identified differentially expressed genes between patients and controls in both cell populations. Dopaminergic neurons had a lower mitochondrial membrane potential than non-dopaminergic neurons. Furthermore, ATP levels were lower in PRKN mutation carriers than controls, and mitochondrial mass was reduced in PRKN mutation carriers only in the TH-positive but not in TH-negative neurons. Importantly, in PRKN mutation carriers, we demonstrated elevated levels of dopamine, which can serve as a significant source of toxic, oxidized dopamine. Using unbiased RNA sequencing, we detected increased levels of CHCHD2 and decreased expression of GPNMB in TH-positive neurons from Parkin mutation carriers compared to healthy controls. This suggests a possible interaction of these three PD genes in response to a dopaminergic neuron-specific increase in oxidative stress, which further leads to the selective vulnerability of dopaminergic neurons.

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