Amyotrophic lateral sclerosis‐associated Vap33 is required for maintaining neuronal dendrite morphology and organelle distribution in <i>Drosophila</i>
Amyotrophic lateral sclerosis‐associated Vap33 is required for maintaining neuronal dendrite morphology and organelle distribution in <i>Drosophila</i>
复制标题
肌萎缩侧索硬化症相关的 Vap33 是维持果蝇神经元树突形态和细胞器分布所必需的
DOI：
10.1111/gtc.12835
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发表时间：
2021
期刊：
影响因子：
2.1
通讯作者：
Chihara Takahiro
中科院分区：
文献类型：
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作者：
Kamemura Kosuke;Chen Chun‐an;Okumura Misako;Miura Masayuki;Chihara Takahiro
VAMP相关蛋白(VAP)是一种内质网(ER)膜蛋白，在内质网与多种细胞内细胞器之间的膜接触部位起着连接蛋白的作用。人类VAPB中的P56S等突变会导致神经退行性疾病，如肌萎缩侧索硬化症(ALS)。然而，VAP在神经元中的功能却鲜为人知。在这里，我们利用带有可抑制细胞标记的镶嵌分析(MARCM)的果蝇嗅觉投射神经元来分析人VAPB的一个同源基因Vap33的神经元功能。在突变型克隆中，投射神经元的树突在保持其形态方面存在缺陷。高尔基体和线粒体的亚细胞定位也异常。这些结果表明，Vap33是神经元形态和细胞器分布所必需的。此外，为了检测ALS相关突变对神经元的影响，我们过表达了人VAPB-P56S invap33ull突变克隆(马赛克救援实验)，发现在老年果蝇中，人VAPB-P56S的表达导致了突触前蛋白BruchPilot的错误定位。这些结果提示突触蛋白的定位和内质网质量控制可能受到疾病突变的影响。我们提供了对VAP在神经元中的生理和病理功能的见解。
VAMP‐associated protein (VAP) is an endoplasmic reticulum (ER) membrane protein that functions as a tethering protein at the membrane contact sites between the ER and various intracellular organelles. Mutations such as P56S in human VAPB cause neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, VAP functions in neurons are poorly understood. Here, we utilizedDrosophilaolfactory projection neurons with a mosaic analysis with a repressible cell marker (MARCM) to analyze the neuronal function of Vap33, aDrosophilaortholog of human VAPB. Invap33null mutant clones, the dendrites of projection neurons exhibited defects in the maintenance of their morphology. The subcellular localization of the Golgi apparatus and mitochondria were also abnormal. These results indicate that Vap33 is required for neuronal morphology and organelle distribution. Additionally, to examine the impact of ALS‐associated mutations in neurons, we overexpressed human VAPB‐P56S invap33null mutant clones (mosaic rescue experiments) and found that, in aged flies, human VAPB‐P56S expression caused mislocalization of Bruchpilot, a presynaptic protein. These results implied that synaptic protein localization and ER quality control may be affected by disease mutations. We provide insights into the physiological and pathological functions of VAP in neurons.