Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons

The end-stage pathology of Parkinson’s disease (PD) involves the loss of dopamine-producing neurons in the substantia nigra  compacta, but synaptic deregulation of these neurons begins much earlier in the disease process. Understanding the mechanisms of axonal deficits may provide opportunities for early therapeutic intervention, yet they remain largely unknown. Within the substantia nigra compacta, different dopamine neuron subpopulations exhibit variable vulnerability patterns in PD, complicating our effort to understand the mechanisms of synaptic dysfunction and vulnerability.  Here, we utilized intersectional genetic mouse models to uncover cell-intrinsic mechanisms of synaptic perturbations in vulnerable dopamine neurons, with a focus on the LRRK2 kinase— an important protein closely linked to PD. A combination of immunofluorescence and advanced proximity labeling methods revealed higher LRRK2 expression in the most vulnerable dopamine neurons.  Further analysis using high-resolution imaging showed that mutant LRRK2 disrupts the release sites of the vulnerable dopamine axons in mice, which correlates with decreased dopamine release in the striatum as reported for these mice. Proteomic and biochemical approaches demonstrate that pathogenic mutant LRRK2 increases the phosphorylation of Rab3 proteins, that are crucial for neurotransmitter release. This alters Rab3 interactions with their effector proteins, impacting their synaptic functions as relevant for neurotransmitter release. Overall, our findings emphasize the cell-autonomous dysfunctions of LRRK2 mutations in the neuronal cell types most impacted in the disease, providing a framework for therapeutic strategies to address early nigrostriatal synaptic deficits in PD.