Kuhlmann Naila, Milnerwood Austen J
Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Front Mol Neurosci. 2020 Aug 27;13:153. doi: 10.3389/fnmol.2020.00153. eCollection 2020.
Since the discovery of mutations causal to Parkinson's disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has helped identify the etiological and pathophysiological underpinnings of the disease, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which links LRRK2 to other genetic forms of PD, most notably those caused by mutations in the synaptic protein α-synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry and eventual death of substantia nigra (SN) neurons. Here, we discuss the evolution and current state of the literature placing LRRK2 at the synapse, through the lens of knock-out, overexpression, and knock-in animal models. We hope that a deeper understanding of LRRK2 neurobiology, at the synapse and beyond, will aid the eventual development of neuroprotective interventions for PD, and the advancement of useful treatments in the interim.
自21世纪初发现导致帕金森病（PD）的突变以来，LRRK2蛋白已被认为参与了众多可能发生发病机制的细胞过程，但其生理功能仍然难以捉摸。LRRK2帕金森病遗传模型的发展有助于确定该疾病的病因和病理生理基础，并可能确定早期干预点。近年来，LRRK2在突触功能中的重要作用已显现出来，这将LRRK2与其他遗传形式的帕金森病联系起来，最显著的是由突触蛋白α-突触核蛋白突变引起的那些形式。这一交汇点可能为驱动基底神经节回路功能障碍和黑质（SN）神经元最终死亡的原因提供有用线索。在此，我们通过基因敲除、过表达和基因敲入动物模型，探讨将LRRK2置于突触处的文献的演变和现状。我们希望，对LRRK2神经生物学在突触及其他方面有更深入的了解，将有助于最终开发针对帕金森病的神经保护干预措施，并在此期间推动有效治疗方法的进步。
