Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease.
Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease.
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DOI：
10.1038/s41467-017-00689-z
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发表时间：
2017-10-30
影响因子：
16.6
通讯作者：
Sendtner M
中科院分区：
文献类型：
--
作者：
Lüningschrör P;Binotti B;Dombert B;Heimann P;Perez-Lara A;Slotta C;Thau-Habermann N;R von Collenberg C;Karl F;Damme M;Horowitz A;Maystadt I;Füchtbauer A;Füchtbauer EM;Jablonka S;Blum R;Üçeyler N;Petri S;Kaltschmidt B;Jahn R;Kaltschmidt C;Sendtner M
自噬介导的突触成分的降解维持了突触的动态平衡，但也构成了神经退行性变的机制。目前尚不清楚突触小泡和突触前活动区成分的自噬是如何受到调控的。在这里，我们证明了包含家族成员5(Plekhg5)的Pleckstrin同源基因(Plekhg5)通过其作为Rab26的鸟嘌呤交换因子的功能来调节运动神经元轴突末端突触小泡的自噬。Rab26是一种小的GTP酶，特异性地将突触小泡定向到自噬前结构。小鼠的Plekhg5基因失活会导致迟发性运动神经元疾病，其特征是轴突终末退化。Plekhg5缺失的培养运动神经元表现出轴突生长缺陷和突触小泡自噬功能受损，这可以通过结构性活性的Rab26来挽救。这些发现定义了一种调节神经元自噬的机制，该机制专门针对突触小泡。这一机制的破坏可能导致几种形式的运动神经元疾病的病理生理学。越来越多的证据表明，自噬的中断与神经退化有关。在这里，作者表明Plekhg5作为Rab26的环境基金，Rab26是一种小的GTP酶，促进神经元中突触小泡的自噬；缺乏Plekhg5的小鼠发生迟发性运动神经元变性。
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease. Accumulating evidence suggests that disruption of autophagy is associated with neurodegeneration. Here the authors show that Plekhg5 acts as a GEF for Rab26, a small GTPase that promotes the autophagy of synaptic vesicles in neurons; mice lacking Plekgh5 develop late-onset motoneuron degeneration.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
3.7
作者：
Bhattacharya S;Pal K;Sharma AK;Dutta SK;Lau JS;Yan IK;Wang E;Elkhanany A;Alkharfy KM;Sanyal A;Patel TC;Chari ST;Spaller MR;Mukhopadhyay D
通讯作者：
Mukhopadhyay D
影响因子：
16.2
作者：
Hernandez D;Torres CA;Setlik W;Cebrián C;Mosharov EV;Tang G;Cheng HC;Kholodilov N;Yarygina O;Burke RE;Gershon M;Sulzer D
通讯作者：
Sulzer D
影响因子：
5.3
作者：
Bruneteau, Gaelle;Bauche, Stephanie;de Aguilar, Jose Luis Gonzalez;Brochier, Guy;Mandjee, Nathalie;Tanguy, Marie-Laure;Hussain, Ghulam;Behin, Anthony;Khiami, Frederic;Sariali, Elhadi;Hell-Remy, Caroline;Salachas, Francois;Pradat, Pierre-Francois;Lacomblez, Lucette;Nicole, Sophie;Fontaine, Bertrand;Fardeau, Michel;Loeffler, Jean-Philippe;Meininger, Vincent;Fournier, Emmanuel;Koenig, Jeanine;Hantai, Daniel
通讯作者：
Hantai, Daniel
影响因子：
20.1
作者：
Garnaas MK;Moodie KL;Liu ML;Samant GV;Li K;Marx R;Baraban JM;Horowitz A;Ramchandran R
通讯作者：
Ramchandran R