Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis.
Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis.
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DOI：
10.1093/hmg/ddt118
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发表时间：
2013-07-01
影响因子：
3.5
通讯作者：
Pennetta G
中科院分区：
文献类型：
--
作者：
Forrest S;Chai A;Sanhueza M;Marescotti M;Parry K;Georgiev A;Sahota V;Mendez-Castro R;Pennetta G
囊泡相关膜蛋白(VAMP)相关蛋白B(VAPB)是人类肌萎缩侧索硬化症(ALS8)的致病基因。肌萎缩侧索硬化症(ALS)是一种以运动神经元选择性死亡为特征的进行性神经退行性疾病，导致痉挛、肌肉萎缩和瘫痪。VAP蛋白参与了多种细胞过程，包括细胞间信号转导、突触重构、脂质转运和膜转运，然而，ALS8发病的分子机制尚不清楚。我们鉴定了保守的磷脂酰肌醇磷酸酶SAC1是果蝇VAP(DVAP)结合伙伴，并表明DVAP是维持正常磷脂酰肌醇水平所必需的。下调SAC1或DVAP会扰乱轴突运输、突触生长、突触微管完整性和几个突触后成分的定位。在ALS8的果蝇模型中，致病等位基因(DVAP-P58S)的表达诱导神经变性，引起类似于DVAP或SAC1下调的突触缺陷，并增加磷脂酰肌醇水平。与SAC1介导的肌醇磷脂水平升高在ALS8发病机制中的作用一致，我们发现SAC1下调以剂量依赖的方式诱导神经变性。此外，我们还报道了SAC1被隔离在DVAP-P58S诱导的聚集体中，降低肌醇磷脂水平可以挽救神经退行性变，并抑制与DVAP-P58S转基因表达相关的突触表型。这些数据强调了DVAP-SAC1相互作用在控制肌醇磷脂代谢中的重要性，并为肌醇磷脂水平在VAP诱导的肌萎缩侧索硬化症中的关键作用提供了机制证据。
The Vesicle-associated membrane protein (VAMP)-Associated Protein B (VAPB) is the causative gene of amyotrophic lateral sclerosis 8 (ALS8) in humans. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective death of motor neurons leading to spasticity, muscle atrophy and paralysis. VAP proteins have been implicated in various cellular processes, including intercellular signalling, synaptic remodelling, lipid transport and membrane trafficking and yet, the molecular mechanisms underlying ALS8 pathogenesis remain poorly understood. We identified the conserved phosphoinositide phosphatase Sac1 as a Drosophila VAP (DVAP)-binding partner and showed that DVAP is required to maintain normal levels of phosphoinositides. Downregulating either Sac1 or DVAP disrupts axonal transport, synaptic growth, synaptic microtubule integrity and the localization of several postsynaptic components. Expression of the disease-causing allele (DVAP-P58S) in a fly model for ALS8 induces neurodegeneration, elicits synaptic defects similar to those of DVAP or Sac1 downregulation and increases phosphoinositide levels. Consistent with a role for Sac1-mediated increase of phosphoinositide levels in ALS8 pathogenesis, we found that Sac1 downregulation induces neurodegeneration in a dosage-dependent manner. In addition, we report that Sac1 is sequestered into the DVAP-P58S-induced aggregates and that reducing phosphoinositide levels rescues the neurodegeneration and suppresses the synaptic phenotypes associated with DVAP-P58S transgenic expression. These data underscore the importance of DVAP–Sac1 interaction in controlling phosphoinositide metabolism and provide mechanistic evidence for a crucial role of phosphoinositide levels in VAP-induced ALS.
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影响因子：
3.5
作者：
De Vos KJ;Mórotz GM;Stoica R;Tudor EL;Lau KF;Ackerley S;Warley A;Shaw CE;Miller CC
通讯作者：
Miller CC
影响因子：
64.5
作者：
Culi, J;Mann, RS
通讯作者：
Mann, RS
DOI：
10.1073/pnas.1005817107
发表时间：
2010-06-29
影响因子：
11.1
作者：
Garrenton, Lindsay S.;Stefan, Christopher J.;Thorner, Jeremy
通讯作者：
Thorner, Jeremy
影响因子：
11.8
作者：
Han, Sung Min;Tsuda, Hiroshi;Miller, Michael A.
通讯作者：
Miller, Michael A.
影响因子：
3.3
作者：
Foti, M;Audhya, A;Emr, SD
通讯作者：
Emr, SD