Selective K-ATP channel-dependent loss of pacemaking in vulnerable nigrostriatal dopamine neurons by α-synuclein aggregates

Parkinson disease (PD), one of the most common neurodegenerative disorder, is believed to be driven by toxic -synuclein aggregates eventually resulting in selective loss of vulnerable neuron populations, prominent among them, nigrostriatal dopamine (DA) neurons in the lateral substantia nigra (l-SN). How -synuclein aggregates initiate a pathophysiological cascade selectively in vulnerable neurons is still unclear. Here, we show that the exposure to low nanomolar concentrations of -synuclein aggregates (i.e. fibrils) but not its monomeric forms acutely and selectively disrupted the electrical pacemaker function of the DA subpopulation most vulnerable in PD. This implies that only dorsolateral striatum projecting l-SN DA neurons were electrically silenced by -synuclein aggregates, while the activity of neither neighboring DA neurons in medial SN projecting to dorsomedial striatum nor mesolimbic DA neurons in the ventral tegmental area (VTA) were affected. Moreover, we demonstrate functional K-ATP channels comprised of Kir6.2 subunit in DA neurons to be necessary to mediate this acute pacemaker disruption by -synuclein aggregates. Our study thus identifies a molecularly defined target that quickly translates the presence of -synuclein aggregates into an immediate impairment of essential neuronal function. This constitutes a novel candidate process how a protein-aggregation-driven sequence in PD is initiated that might eventually lead to selective neurodegeneration.