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 pars compacta (SNc). However, synaptic deregulation of these neurons begins much earlier. Understanding the mechanisms behind synaptic deficits is crucial for early therapeutic intervention, yet these remain largely unknown. In the SNc, different dopamine neuron subtypes show varying susceptibility patterns to PD, complicating our understanding. This study uses intersectional genetic mouse models to uncover synaptic perturbations in vulnerable dopamine neurons, focusing on the LRRK2 kinase, a protein closely linked to PD. Through a combination of immunofluorescence and advanced proximity labeling methods, we found higher LRRK2 expression in the most vulnerable dopamine neuron subclusters. High-resolution imaging revealed that pathogenic LRRK2 disrupts release sites in vulnerable dopamine axons, leading to decreased in vivo evoked striatal dopamine release in mice with LRRK2 mutations. Proteomic and biochemical analyses indicate that mutant LRRK2 increases the phosphorylation of RAB3 proteins, reducing their interactions with RIM1/2 effector proteins and impacting their synaptic functions. Overall, this research highlights the cell-autonomous dysfunctions caused by mutant LRRK2 in the neurons that are primarily affected by the disease. It also provides a framework for therapeutic strategies for early nigrostriatal synaptic deficits in PD.
Authors
- Amir R. Khan (ORCID: https://orcid.org/0000-0003-1176-6952)
- Vanessa Promes (ORCID: https://orcid.org/0000-0002-9078-6232)
- Oscar Andrés Moreno-Ramos (ORCID: https://orcid.org/0000-0002-1378-2545)
- Daniel A. Dombeck (ORCID: https://orcid.org/0000-0003-2576-5918)
- Yahaira Naaldijk (ORCID: https://orcid.org/0000-0003-2701-3963)
- Giulia Tombesi (ORCID: https://orcid.org/0000-0003-0683-8050)
- Qianzi He (ORCID: https://orcid.org/0000-0002-4607-166X)
- Matthew Jaconelli (ORCID: https://orcid.org/0009-0003-1536-435X)
- Hannah Serio (ORCID: https://orcid.org/0000-0002-9845-3205)
- Dario R. Alessi (ORCID: https://orcid.org/0000-0002-2140-9185)
- Elisa Greggio (ORCID: https://orcid.org/0000-0002-8172-3598)
- Yevgenia Kozorovitskiy (ORCID: https://orcid.org/0000-0002-3710-1484)
- Sabine Hilfiker (ORCID: https://orcid.org/0000-0002-5167-7682)
- Chuyu Chen (ORCID: https://orcid.org/0000-0001-5666-5173)
- Loukia Parisiadou (ORCID: https://orcid.org/0000-0002-2569-4200)
- Daniel Arango (ORCID: https://orcid.org/0000-0001-9523-830X)
- Rajeshwar Awatramani (ORCID: https://orcid.org/0000-0002-0713-2140)
- Amanda Schneeweis (ORCID: https://orcid.org/0000-0003-4141-6064)
- Eve Napier (ORCID: https://orcid.org/0000-0002-2667-2652)
- Christopher Nasios
Institutions
- Rutgers, The State University of New Jersey (US)
- Northwestern University (US)
- University of Padua (IT)
- University of Dundee (GB)
- Trinity College Dublin (IE)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Research Network (United States) (US)
- Rutgers New Jersey Medical School (US)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-28
- DOI
- https://doi.org/10.1038/s41467-026-75194-3
- Citations
- 1
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.04
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Northwestern University
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- Medical Research Council