Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons.
Endogenous Leucine-Rich Repeat Kinase 2 Slows Synaptic Vesicle Recycling in Striatal Neurons.
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DOI：
10.3389/fnsyn.2017.00005
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发表时间：
2017
影响因子：
3.7
通讯作者：
Edwards RH
中科院分区：
文献类型：
--
作者：
Maas JW;Yang J;Edwards RH
富亮氨酸重复激酶2 （LRRK2）的显性突变产生最常见的遗传性帕金森病（PD），但LRRK2的功能仍然知之甚少。包括α-突触核蛋白（α-syn）在内的多个与PD相关的基因在突触前的作用表明，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，使用引起毒性的疾病相关突变体使分析复杂化。为了确定LRRK2是否正常影响突触囊泡，我们现在使用成像和电生理学相结合的方法来研究LRRK2敲除（KO）小鼠。令人惊讶的是，我们发现在海马（通常是兴奋性）神经元中，LRRK2的缺失并不影响突触囊泡的胞外分泌、内吞作用或α-syn的移动性。缺乏LRRK1和LRRK2的双KO （DKO）小鼠海马神经元的递质释放也没有缺陷。然而，在纹状体神经元中，LRRK2的表达水平较高，LRRK2的缺失会导致突触囊泡内吞的适度加速。因此，内源性LRRK2通常会减缓纹状体末端的突触囊泡循环。
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.