Parkinson's disease (PD) is the fastest growing neurodegenerative disease worldwide, while Neurodegeneration with Brain Iron Accumulation (NBIA) disorders are very rare. A major hallmark in both diseases is the death of dopaminergic neurons in the midbrain. There are still no causal therapies available to halt or slow down this neurodegeneration. The progressive course of this disease is difficult to understand in conventional animal or cell culture models. However, this is of crucial importance in order to develop causal therapies for early intervention in the disease processes.
In my recent work, we discovered a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidation of dopamine (DA) and ultimately resulting in lysosomal dysfunction in induced pluripotent stem cell (iPSC)-derived DA neurons from PD patients (Burbulla et al., Science, 2017). This work uncovered DA oxidation (oxidation occurring when DA is improperly packaged into synaptic vesicles and stays in the cytosol) as a major mediator of dysfunction in multiple forms of PD. Importantly, this pathogenic cascade was not found in PD mouse models due to species-specific differences in DA metabolism, a fact that may - at least in part - explain relative resistance of rodent neurons to degeneration in genetic models of PD.
The mechanism of toxicity of cytosolic DA that predisposes human neurons to selective vulnerability and degeneration is unknown and studies on human neurons are needed for understanding disease progression and development of therapeutics. In fact, one of the most promising advantages of human iPSCs is their utility as a patient-specific disease model, offering the opportunity to gain deeper insights into disease mechanisms and progression.
In oxDOPAMINE we use PD and BPAN (subtype of Neurodegeneration with Brain Iron Accumulation, NBIA) patient-derived neurons to uncover the origin and nature of DA oxidation that predisposes human neurons to selective vulnerability and degeneration. We hypothesize that defective synaptic DA metabolism and iron dyshomeostasis play a critical role in the oxidation of cytosolic DA early in disease pathogenesis. A unifying feature of these pathogenic mechanisms is that impaired handling of DA contributes to toxicity of DA neurons. oxDOPAMINE will be of broad significance to a large cohort of patients with neurodegenerative diseases as it will advance our understanding of whether restoration of synaptic dysfunction and iron metabolism may prevent midbrain DA neurodegeneration, to represent a potential therapeutic target.
