Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Chicago, US · Author affiliation
Department of Pharmacology, Northwestern University, Chicago, IL, USA.Location evidence
US · Author affiliation · country only
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.Location evidence
Evanston, US · Author affiliation
Department of Neurobiology, Northwestern University, Evanston, IL, USA.Location evidence
Dublin, IE · Author affiliation
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.Location evidence
Dundee, GB · Author affiliation
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.Location evidence
JE · Author affiliation · country only
Department of Anesthesiology, Rutgers, New Jersey Medical School, Newark, NJ, USA.Location evidence
IT · Author affiliation · country only
Department of Biology, University of Padova, Padova, Italy.Location evidence
Centro, IT · Author affiliation
Centro Studi per la Neurodegenerazione (CESNE), University of Padova, Padova, Italy.Location evidence
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Original abstract
Parkinson's disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. Here, we used intersectional genetic mouse models to determine how the PD-linked kinase LRRK2 affects vulnerable dopamine subtypes. Immunofluorescence and proximity-labeling proteomics revealed enriched LRRK2 expression in vulnerable dopamine neuron subclusters. High-resolution imaging showed that pathogenic LRRK2 disrupts presynaptic release-site organization in vulnerable dopamine axons, leading to reduced spontaneous and evoked striatal dopamine release in vivo. Proteomic analyses further showed that mutant LRRK2 increases phosphorylation of RAB3 proteins, impairing their interaction with the active-zone effectors RIM1 and RIM2. Together, these findings highlight a subtype-specific, cell-autonomous mechanism by which pathogenic LRRK2 impairs PD-vulnerable nigrostriatal synapses and provide a framework for therapeutic strategies targeting early synaptic deficits in PD.