Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila
Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila
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DOI：
10.1093/hmg/ddx179
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Inoshita, Tsuyoshi;Arano, Taku;Hattori, Nobutaka
逆转录成分Vps35和内体激酶LRRK2的突变与家族性帕金森病（PD）的常染色体显性形式有关。然而，Vps35和LRRK2在神经元功能中的生理和病理作用尚不清楚。在这里，我们证明了果蝇Vps35 （dVps35）的缺失会影响突触囊泡循环、多巴胺能突触释放和与多巴胺能活性相关的睡眠行为，这是由野生型dVps35而不是pd相关突变型dVps35 D647N的表达所拯救的。果蝇LRRK2 dLRRK连同Rab5和Rab11也与突触囊泡循环有关，操纵这些活动可改善Vps35突触表型。这些发现表明突触囊泡循环缺陷可能是PD病因的关键因素，其中两个晚发性PD基因Vps35和LRRK2参与其中。
Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms of familial Parkinson's disease (PD). However, the physiological and pathological roles of Vps35 and LRRK2 in neuronal functions are poorly understood. Here, we demonstrated that the loss of Drosophila Vps35 (dVps35) affects synaptic vesicle recycling, dopaminergic synaptic release and sleep behavior associated with dopaminergic activity, which is rescued by the expression of wild-type dVps35 but not the PD-associated mutant dVps35 D647N. Drosophila LRRK2 dLRRK together with Rab5 and Rab11 is also implicated in synaptic vesicle recycling, and the manipulation of these activities improves the Vps35 synaptic phenotypes. These findings indicate that defects of synaptic vesicle recycling in which two late-onset PD genes, Vps35 and LRRK2, are involved could be key aspects of PD etiology.