While the cellular mechanisms involved in SN DA neurodegeneration are still not completely understood in PD, we recently identified a pathological cascade involving mitochondrial oxidant stress and oxidized DA that drives multiple downstream neurotoxic phenotypes in PD patient- derived neurons. Here, we propose to investigate the upstream mechanistic pathways leading to this oxidized DA accumulation in PD using imaging, biochemical and electrophysiological approaches in long-term cultures of patient-derived DA neurons. As recent genetic studies have identified synaptic genes linked to PD, our first aim will determine whether familial PD genes including parkin and LRRK2 interact with PD-linked synaptic genes to modulate synaptic vesicle endocytosis. In our second aim, we will analyze whether sporadic PD modeled by mitochondrial Complex I deficiency leads to defective synaptic vesicle turnover due to loss of synaptic ATP production. In both aims, our working hypothesis is that defects in synaptic vesicle endocytosis prevents efficient cytosolic DA uptake and, in the presence of mitochondrial oxidant stress, this deficit results in the accumulation of cytosolic oxidized DA and downstream pathogenic phenotypes. Finally, our third aim is to determine whether glutamatergic signaling through metabotropic glutamatergic receptors further drives mitochondrial oxidant stress and DA oxidation. Increased glutamatergic signaling arising from the STN and PPN could promote degeneration of SN DA neurons in the later stages of PD, but it is unclear whether the mechanisms present in rodent SN DA neurons are recapitulated in human neurons. Together, these aims will further inform the mechanisms studied in Projects 1 and 2, and elucidate their role in driving mitochondrial stress, oxidized DA accumulation and downstream PD pathogenesis in human DA neurons.
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