Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
J Neurosci. 2010 Dec 15;30(50):16959-69. doi: 10.1523/JNEUROSCI.1807-10.2010.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial as well as sporadic forms of Parkinson's disease (PD), a neurodegenerative disease characterized by dysfunction and degeneration of dopaminergic and other types of neurons. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Here, we show that LRRK2 controls synaptic morphogenesis at the Drosophila neuromuscular junction. Loss of Drosophila LRRK2 results in synaptic overgrowth, whereas overexpression of Drosophila LRRK or human LRRK2 has opposite effects. Alteration of LRRK2 activity also affects neurotransmission. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the presynaptic and postsynaptic compartments. At the postsynapse, LRRK2 interacts with the previously characterized substrate 4E-BP, an inhibitor of protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule (MT)-binding protein Futsch. These results implicate synaptic dysfunction caused by deregulated protein synthesis and aberrant MT dynamics in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating PD.
富含亮氨酸重复激酶 2 (LRRK2) 的突变与家族性和散发性帕金森病 (PD) 有关，PD 是一种神经退行性疾病，其特征是多巴胺能神经元和其他类型神经元的功能障碍和退化。LRRK2 作用的分子和细胞机制仍未得到很好的定义。在这里，我们表明 LRRK2 控制果蝇肌肉神经接点的突触形态发生。果蝇 LRRK2 的缺失导致突触过度生长，而果蝇 LRRK 或人 LRRK2 的过表达则具有相反的效果。LRRK2 活性的改变也会影响神经传递。LRRK2 通过与突触前和突触后区的不同下游效应物相互作用，对突触形态产生影响。在突触后，LRRK2 与先前表征的底物 4E-BP 相互作用，4E-BP 是蛋白质合成的抑制剂。在突触前，LRRK2 磷酸化并负调控微管 (MT)-结合蛋白 Futsch。这些结果表明，由蛋白质合成失调和异常的 MT 动力学引起的突触功能障碍在 LRRK2 的发病机制中起作用，并为理解和最终治疗 PD 提供了一个新的范例。
