PICALM modulates autophagy activity and tau accumulation.
PICALM modulates autophagy activity and tau accumulation.
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DOI：
10.1038/ncomms5998
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发表时间：
2014-09-22
影响因子：
16.6
通讯作者：
Rubinsztein, David C.
中科院分区：
文献类型：
--
作者：
Moreau, Kevin;Fleming, Angeleen;Imarisio, Sara;Ramirez, Ana Lopez;Mercer, Jacob L.;Jimenez-Sanchez, Maria;Bento, Carla F.;Puri, Claudia;Zavodszky, Eszter;Siddiqi, Farah;Lavau, Catherine P.;Betton, Maureen;O'Kane, Cahir J.;Wechsler, Daniel S.;Rubinsztein, David C.
全基因组关联研究已经确定了与阿尔茨海默病（AD）相关的几个基因座，包括参与内吞运输的蛋白质，例如PICALM/CALM（磷脂酰肌醇结合网格蛋白组装蛋白）。目前还不清楚这些基因座如何可能有助于AD病理。在这里，我们表明，CALM调节自噬和改变tau蛋白的清除，这是一种已知的自噬底物，并在体外和体内与AD有因果关系。此外，改变的CALM表达加剧了斑马鱼转基因模型中tau介导的毒性。CALM通过调节SNARE（如VAMP 2、VAMP 3和VAMP 8）的内吞作用来影响自噬，这些SNARE对自噬途径的不同阶段（从自噬体形成到自噬体降解）具有不同的影响。这项研究表明，AD遗传风险因子CALM调节自噬，这可能会影响疾病的多种方式，包括调节tau蛋白的周转。 蛋白质PICALM/CALM与阿尔茨海默病（AD）病理学有关，但尚不清楚如何。在这项研究中，作者表明CALM通过促进内吞依赖性自噬来调节tau蛋白的清除，这也与AD病理学有关。
Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover. The protein PICALM/CALM is implicated in Alzheimer’s disease (AD) pathology, but it is unclear how. In this study, the authors show that CALM regulates clearance of the protein tau, which is also implicated in AD pathology, by facilitating endocytosis-dependent autophagy.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
4.2
作者：
Lambert, Jean-Charles;Zelenika, Diana;Amouyel, Philippe
通讯作者：
Amouyel, Philippe
影响因子：
64.5
作者：
Freeman, M
通讯作者：
Freeman, M
影响因子：
12.7
作者：
Ando, Kunie;Brion, Jean-Pierre;Duyckaerts, Charles
通讯作者：
Duyckaerts, Charles