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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月28日

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  • Chuyu Chen,
  • Qianzi He,
  • Giulia Tombesi,
  • Eve Napier,
  • Matthew Jaconelli,
  • Oscar Andrés Moreno-Ramos,
  • Hannah Serio,
  • Yahaira Naaldijk,
  • Vanessa Promes,
  • Amanda Schneeweis,
  • Kaitlyn Quinn,
  • Christopher Nasios,
  • Elisa Greggio,
  • Yevgenia Kozorovitskiy,
  • Daniel Arango,
  • Amir R. Khan,
  • Dario R. Alessi,
  • Daniel A. Dombeck,
  • Sabine Hilfiker,
  • Rajeshwar Awatramani,
  • Loukia Parisiadou

摘要

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.