Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila.
Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila.
复制标题
DOI：
10.1016/j.isci.2022.105476
复制
发表时间：
2022-12-22
期刊：
影响因子：
5.8
通讯作者：
Imai, Yuzuru
中科院分区：
文献类型：
--
作者：
Inoshita, Tsuyoshi;Liu, Jun-Yi;Taniguchi, Daisuke;Ishii, Ryota;Hattori, Kahori Shiba-Nobutaka;Hattori, Nobutaka;Imai, Yuzuru
一些帕金森病（PD）致病/危险基因，包括PD相关激酶富亮氨酸重复激酶2 (LRRK2)，参与了膜动力学。尽管LRRK2和其他pd相关基因被认为调节突触功能、轴突运输和内溶酶体活性，但是否存在共同的病理途径尚不清楚。在这里，我们报道了Lrrk（人类LRRK2的同源物）的缺失导致了果蝇中溶酶体相关的细胞器调节因子ar18的积累，以及神经元末端最远端扣密集的核心囊泡。此外，一个小的GTPase Rab3的失活和辅助素活性的改变导致了ar18的积累。ar18阳性囊泡的积累依赖于unc -104，并受pd相关基因、Auxilin、VPS35、RME-8和INPP5F的调节，表明VPS35、RME-8和INPP5F是Lrrk的上游调节因子。这些结果表明，某些pd相关基因与LRRK2一起驱动致密核心囊泡的精确神经轴突运输。LRRK突变导致果蝇突触前Arl8样GTPase Arl8积累，Arl8积累与致密的核心囊泡有关，UNC-104依赖性pd相关基因VPS35、RME-8、Auxilin和INPP5F参与Arl8动力学。遗传学;神经科学;细胞生物学
Some Parkinson’s disease (PD)-causative/risk genes, including the PD-associated kinase leucine-rich repeat kinase 2 (LRRK2), are involved in membrane dynamics. Although LRRK2 and other PD-associated genes are believed to regulate synaptic functions, axonal transport, and endolysosomal activity, it remains unclear whether a common pathological pathway exists. Here, we report that the loss of Lrrk, an ortholog of human LRRK2, leads to the accumulation of the lysosome-related organelle regulator, Arl8 along with dense core vesicles at the most distal boutons of the neuron terminals in Drosophila. Moreover, the inactivation of a small GTPase Rab3 and altered Auxilin activity phenocopied Arl8 accumulation. The accumulation of Arl8-positive vesicles is UNC-104-dependent and modulated by PD-associated genes, Auxilin, VPS35, RME-8, and INPP5F, indicating that VPS35, RME-8, and INPP5F are upstream regulators of Lrrk. These results indicate that certain PD-related genes, along with LRRK2, drive precise neuroaxonal transport of dense core vesicles. LRRK mutations lead to Arf-like GTPase Arl8 accumulation at presynapses in Drosophila Arl8 accumulation is associated with dense core vesicles and UNC-104 dependent PD-related genes VPS35, RME-8, Auxilin, and INPP5F are involved in Arl8 dynamics Biological sciences; Genetics; Neuroscience; Cell biology
登录
查看更多内容
影响因子：
3.3
作者：
Ding J;Segarra VA;Chen S;Cai H;Lemmon SK;Ferro-Novick S
通讯作者：
Ferro-Novick S
影响因子：
4.5
作者：
Choudhary B;Kamak M;Ratnakaran N;Kumar J;Awasthi A;Li C;Nguyen K;Matsumoto K;Hisamoto N;Koushika SP
通讯作者：
Koushika SP
影响因子：
3.3
作者：
Burgess J;Jauregui M;Tan J;Rollins J;Lallet S;Leventis PA;Boulianne GL;Chang HC;Le Borgne R;Krämer H;Brill JA
通讯作者：
Brill JA
DOI：
10.1083/jcb.200311084
发表时间：
2004-03-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chang HC;Hull M;Mellman I
通讯作者：
Mellman I
DOI：
10.1073/pnas.0509844103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Grabner, Chad P.;Price, Steven D.;Fox, Aaron P.
通讯作者：
Fox, Aaron P.