VMAT2 dysfunction impairs vesicular dopamine sequestration, driving oxidation and α-synuclein pathology in DJ-1-linked Parkinson’s disease neurons

Parkinson’s disease (PD) is characterized by the selective degeneration of dopaminergic neurons in the substantia nigra, yet its underlying molecular mechanism remains unclear. Excessive dopamine oxidation is a pathological hallmark observed in various forms of PD. Mutations in PD-associated genes, such as DJ-1, underscore the critical role of mitochondrial bioenergetics in PD pathogenesis, potentially causing mitochondrial oxidant stress and increased dopamine oxidation. Given that DJ-1 KO and LoF mutations in the gene are associated with Parkinsonism, the molecular mechanism of DJ-1's involvement is being investigated in DJ-1 KO hiPSC-derived dopaminergic neurons. DJ-1 KO neurons exhibit a number of morphological and functional defects at the synapse, which could either be driven directly by DJ-1's interaction with synaptic proteins or, indirectly, by the effects of its loss on mitochondrial metabolism. In order to validate either of these hypothesis and map the physiological interactions of DJ-1, disrupted upon its KO, we have performed IP-MS experiments using endogenous untagged DJ-1 as the bait, with a particular interest towards its synaptic interactome in dopaminergic neurons.