Maas James W Jr, Yang Jing, Edwards Robert H
Departments of Neurology and Physiology, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, UCSF School of Medicine San Francisco, CA, USA.
Front Synaptic Neurosci. 2017 Feb 23;9:5. doi: 10.3389/fnsyn.2017.00005. eCollection 2017.
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) produce the most common inherited form of Parkinson's disease (PD) but the function of LRRK2 remains poorly understood. The presynaptic role of multiple genes linked to PD including α-synuclein (α-syn) has suggested that LRRK2 may also influence neurotransmitter release, a possibility supported by recent work. However, the use of disease-associated mutants that cause toxicity complicates the analysis. To determine whether LRRK2 normally influences the synaptic vesicle, we have now used a combination of imaging and electrophysiology to study LRRK2 knockout (KO) mice. Surprisingly, we find that in hippocampal (generally excitatory) neurons, the loss of LRRK2 does not affect synaptic vesicle exocytosis, endocytosis or the mobility of α-syn. Double KO (DKO) mice lacking LRRK1 as well as LRRK2 also show no defect in transmitter release by hippocampal neurons. However, in striatal neurons, which express LRRK2 at higher levels, the loss of LRRK2 leads to modest acceleration of synaptic vesicle endocytosis. Thus, endogenous LRRK2 normally slows synaptic vesicle recycling at striatal terminals.
富含亮氨酸重复激酶2（LRRK2）中的显性突变会导致帕金森病（PD）最常见的遗传形式，但LRRK2的功能仍知之甚少。包括α-突触核蛋白（α-syn）在内的多个与PD相关基因的突触前作用表明，LRRK2也可能影响神经递质释放，最近的研究支持了这一可能性。然而，使用会导致毒性的疾病相关突变体使分析变得复杂。为了确定LRRK2是否正常影响突触小泡，我们现在结合成像和电生理学方法来研究LRRK2基因敲除（KO）小鼠。令人惊讶的是，我们发现在海马体（通常为兴奋性）神经元中，LRRK2的缺失并不影响突触小泡的胞吐作用、内吞作用或α-syn的移动性。同时缺乏LRRK1和LRRK2的双基因敲除（DKO）小鼠的海马体神经元在神经递质释放方面也没有缺陷。然而，在LRRK2表达水平较高的纹状体神经元中，LRRK2的缺失会导致突触小泡内吞作用适度加速。因此，内源性LRRK2通常会减缓纹状体终末的突触小泡循环。
