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A gene toolbox for monitoring autophagy transcription

Bordi, Matteo; De Cegli, Rossella; Testa, Beatrice; Nixon, Ralph A; Ballabio, Andrea; Cecconi, Francesco
Autophagy is a highly dynamic and multi-step process, regulated by many functional protein units. Here, we have built up a comprehensive and up-to-date annotated gene list for the autophagy pathway, by combining previously published gene lists and the most recent publications in the field. We identified 604 genes and created main categories: MTOR and upstream pathways, autophagy core, autophagy transcription factors, mitophagy, docking and fusion, lysosome and lysosome-related genes. We then classified such genes in sub-groups, based on their functions or on their sub-cellular localization. Moreover, we have curated two shorter sub-lists to predict the extent of autophagy activation and/or lysosomal biogenesis; we next validated the "induction list" by Real-time PCR in cell lines during fasting or MTOR inhibition, identifying ATG14, ATG7, NBR1, ULK1, ULK2, and WDR45, as minimal transcriptional targets. We also demonstrated that our list of autophagy genes can be particularly useful during an effective RNA-sequencing analysis. Thus, we propose our lists as a useful toolbox for performing an informative and functionally-prognostic gene scan of autophagy steps.
PMID: 34728604
ISSN: 2041-4889
CID: 5038062

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

Yuan, Aidong; Nixon, Ralph A.
Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits "“ neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer"™s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.
ISSN: 1662-4548
CID: 5056062

Alzheimer disease

Knopman, David S; Amieva, Helene; Petersen, Ronald C; Chételat, Gäel; Holtzman, David M; Hyman, Bradley T; Nixon, Ralph A; Jones, David T
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
PMID: 33986301
ISSN: 2056-676x
CID: 4889382

Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons

Lie, Pearl P Y; Yang, Dun-Sheng; Stavrides, Philip; Goulbourne, Chris N; Zheng, Ping; Mohan, Panaiyur S; Cataldo, Anne M; Nixon, Ralph A
Lysosomal trafficking and maturation in neurons remain poorly understood and are unstudied in vivo despite high disease relevance. We generated neuron-specific transgenic mice to track vesicular CTSD acquisition, acidification, and traffic within the autophagic-lysosomal pathway in vivo, revealing that mature lysosomes are restricted from axons. Moreover, TGN-derived transport carriers (TCs), not lysosomes, supply lysosomal components to axonal organelles. Ultrastructurally distinctive TCs containing TGN and lysosomal markers enter axons, engaging autophagic vacuoles and late endosomes. This process is markedly upregulated in dystrophic axons of Alzheimer models. In cultured neurons, most axonal LAMP1 vesicles are weakly acidic TCs that shuttle lysosomal components bidirectionally, conferring limited degradative capability to retrograde organelles before they mature fully to lysosomes within perikarya. The minor LAMP1 subpopulation attaining robust acidification are retrograde Rab7+ endosomes/amphisomes, not lysosomes. Restricted lysosome entry into axons explains the unique lysosome distribution in neurons and their vulnerability toward neuritic dystrophy in disease.
PMID: 33910020
ISSN: 2211-1247
CID: 4853382

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Klionsky, Daniel J; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud; Abdoli, Asghar; Abel, Steffen; Abeliovich, Hagai; Abildgaard, Marie H; Abudu, Yakubu Princely; Acevedo-Arozena, Abraham; Adamopoulos, Iannis E; Adeli, Khosrow; Adolph, Timon E; Adornetto, Annagrazia; Aflaki, Elma; Agam, Galila; Agarwal, Anupam; Aggarwal, Bharat B; Agnello, Maria; Agostinis, Patrizia; Agrewala, Javed N; Agrotis, Alexander; Aguilar, Patricia V; Ahmad, S Tariq; Ahmed, Zubair M; Ahumada-Castro, Ulises; Aits, Sonja; Aizawa, Shu; Akkoc, Yunus; Akoumianaki, Tonia; Akpinar, Hafize Aysin; Al-Abd, Ahmed M; Al-Akra, Lina; Al-Gharaibeh, Abeer; Alaoui-Jamali, Moulay A; Alberti, Simon; Alcocer-Gómez, Elísabet; Alessandri, Cristiano; Ali, Muhammad; Alim Al-Bari, M Abdul; Aliwaini, Saeb; Alizadeh, Javad; Almacellas, Eugènia; Almasan, Alexandru; Alonso, Alicia; Alonso, Guillermo D; Altan-Bonnet, Nihal; Altieri, Dario C; Álvarez, Élida M C; Alves, Sara; Alves da Costa, Cristine; Alzaharna, Mazen M; Amadio, Marialaura; Amantini, Consuelo; Amaral, Cristina; Ambrosio, Susanna; Amer, Amal O; Ammanathan, Veena; An, Zhenyi; Andersen, Stig U; Andrabi, Shaida A; Andrade-Silva, Magaiver; Andres, Allen M; Angelini, Sabrina; Ann, David; Anozie, Uche C; Ansari, Mohammad Y; Antas, Pedro; Antebi, Adam; Antón, Zuriñe; Anwar, Tahira; Apetoh, Lionel; Apostolova, Nadezda; Araki, Toshiyuki; Araki, Yasuhiro; Arasaki, Kohei; Araújo, Wagner L; Araya, Jun; Arden, Catherine; Arévalo, Maria-Angeles; Arguelles, Sandro; Arias, Esperanza; Arikkath, Jyothi; Arimoto, Hirokazu; Ariosa, Aileen R; Armstrong-James, Darius; Arnauné-Pelloquin, Laetitia; Aroca, Angeles; Arroyo, Daniela S; Arsov, Ivica; Artero, Rubén; Asaro, Dalia Maria Lucia; Aschner, Michael; Ashrafizadeh, Milad; Ashur-Fabian, Osnat; Atanasov, Atanas G; Au, Alicia K; Auberger, Patrick; Auner, Holger W; Aurelian, Laure; Autelli, Riccardo; Avagliano, Laura; Ávalos, Yenniffer; Aveic, Sanja; Aveleira, Célia Alexandra; Avin-Wittenberg, Tamar; Aydin, Yucel; Ayton, Scott; Ayyadevara, Srinivas; Azzopardi, Maria; Baba, Misuzu; Backer, Jonathan M; Backues, Steven K; Bae, Dong-Hun; Bae, Ok-Nam; Bae, Soo Han; Baehrecke, Eric H; Baek, Ahruem; Baek, Seung-Hoon; Baek, Sung Hee; Bagetta, Giacinto; Bagniewska-Zadworna, Agnieszka; Bai, Hua; Bai, Jie; Bai, Xiyuan; Bai, Yidong; Bairagi, Nandadulal; Baksi, Shounak; Balbi, Teresa; Baldari, Cosima T; Balduini, Walter; Ballabio, Andrea; Ballester, Maria; Balazadeh, Salma; Balzan, Rena; Bandopadhyay, Rina; Banerjee, Sreeparna; Banerjee, Sulagna; Bánréti, Ágnes; Bao, Yan; Baptista, Mauricio S; Baracca, Alessandra; Barbati, Cristiana; Bargiela, Ariadna; Barilà, Daniela; Barlow, Peter G; Barmada, Sami J; Barreiro, Esther; Barreto, George E; Bartek, Jiri; Bartel, Bonnie; Bartolome, Alberto; Barve, Gaurav R; Basagoudanavar, Suresh H; Bassham, Diane C; Bast, Robert C; Basu, Alakananda; Batoko, Henri; Batten, Isabella; Baulieu, Etienne E; Baumgarner, Bradley L; Bayry, Jagadeesh; Beale, Rupert; Beau, Isabelle; Beaumatin, Florian; Bechara, Luiz R G; Beck, George R; Beers, Michael F; Begun, Jakob; Behrends, Christian; Behrens, Georg M N; Bei, Roberto; Bejarano, Eloy; Bel, Shai; Behl, Christian; Belaid, Amine; Belgareh-Touzé, Naïma; Bellarosa, Cristina; Belleudi, Francesca; Belló Pérez, Melissa; Bello-Morales, Raquel; Beltran, Jackeline Soares de Oliveira; Beltran, Sebastián; Benbrook, Doris Mangiaracina; Bendorius, Mykolas; Benitez, Bruno A; Benito-Cuesta, Irene; Bensalem, Julien; Berchtold, Martin W; Berezowska, Sabina; Bergamaschi, Daniele; Bergami, Matteo; Bergmann, Andreas; Berliocchi, Laura; Berlioz-Torrent, Clarisse; Bernard, Amélie; Berthoux, Lionel; Besirli, Cagri G; Besteiro, Sebastien; Betin, Virginie M; Beyaert, Rudi; Bezbradica, Jelena S; Bhaskar, Kiran; Bhatia-Kissova, Ingrid; Bhattacharya, Resham; Bhattacharya, Sujoy; Bhattacharyya, Shalmoli; Bhuiyan, Md Shenuarin; Bhutia, Sujit Kumar; Bi, Lanrong; Bi, Xiaolin; Biden, Trevor J; Bijian, Krikor; Billes, Viktor A; Binart, Nadine; Bincoletto, Claudia; Birgisdottir, Asa B; Bjorkoy, Geir; Blanco, Gonzalo; Blas-Garcia, Ana; Blasiak, Janusz; Blomgran, Robert; Blomgren, Klas; Blum, Janice S; Boada-Romero, Emilio; Boban, Mirta; Boesze-Battaglia, Kathleen; Boeuf, Philippe; Boland, Barry; Bomont, Pascale; Bonaldo, Paolo; Bonam, Srinivasa Reddy; Bonfili, Laura; Bonifacino, Juan S; Boone, Brian A; Bootman, Martin D; Bordi, Matteo; Borner, Christoph; Bornhauser, Beat C; Borthakur, Gautam; Bosch, Jürgen; Bose, Santanu; Botana, Luis M; Botas, Juan; Boulanger, Chantal M; Boulton, Michael E; Bourdenx, Mathieu; Bourgeois, Benjamin; Bourke, Nollaig M; Bousquet, Guilhem; Boya, Patricia; Bozhkov, Peter V; Bozi, Luiz H M; Bozkurt, Tolga O; Brackney, Doug E; Brandts, Christian H; Braun, Ralf J; Braus, Gerhard H; Bravo-Sagua, Roberto; Bravo-San Pedro, José M; Brest, Patrick; Bringer, Marie-Agnès; Briones-Herrera, Alfredo; Broaddus, V Courtney; Brodersen, Peter; Brodsky, Jeffrey L; Brody, Steven L; Bronson, Paola G; Bronstein, Jeff M; Brown, Carolyn N; Brown, Rhoderick E; Brum, Patricia C; Brumell, John H; Brunetti-Pierri, Nicola; Bruno, Daniele; Bryson-Richardson, Robert J; Bucci, Cecilia; Buchrieser, Carmen; Bueno, Marta; Buitrago-Molina, Laura Elisa; Buraschi, Simone; Buch, Shilpa; Buchan, J Ross; Buckingham, Erin M; Budak, Hikmet; Budini, Mauricio; Bultynck, Geert; Burada, Florin; Burgoyne, Joseph R; Burón, M Isabel; Bustos, Victor; Büttner, Sabrina; Butturini, Elena; Byrd, Aaron; Cabas, Isabel; Cabrera-Benitez, Sandra; Cadwell, Ken; Cai, Jingjing; Cai, Lu; Cai, Qian; Cairó, Montserrat; Calbet, Jose A; Caldwell, Guy A; Caldwell, Kim A; Call, Jarrod A; Calvani, Riccardo; Calvo, Ana C; Calvo-Rubio Barrera, Miguel; Camara, Niels Os; Camonis, Jacques H; Camougrand, Nadine; Campanella, Michelangelo; Campbell, Edward M; Campbell-Valois, François-Xavier; Campello, Silvia; Campesi, Ilaria; Campos, Juliane C; Camuzard, Olivier; Cancino, Jorge; Candido de Almeida, Danilo; Canesi, Laura; Caniggia, Isabella; Canonico, Barbara; Cantí, Carles; Cao, Bin; Caraglia, Michele; Caramés, Beatriz; Carchman, Evie H; Cardenal-Muñoz, Elena; Cardenas, Cesar; Cardenas, Luis; Cardoso, Sandra M; Carew, Jennifer S; Carle, Georges F; Carleton, Gillian; Carloni, Silvia; Carmona-Gutierrez, Didac; Carneiro, Leticia A; Carnevali, Oliana; Carosi, Julian M; Carra, Serena; Carrier, Alice; Carrier, Lucie; Carroll, Bernadette; Carter, A Brent; Carvalho, Andreia Neves; Casanova, Magali; Casas, Caty; Casas, Josefina; Cassioli, Chiara; Castillo, Eliseo F; Castillo, Karen; Castillo-Lluva, Sonia; Castoldi, Francesca; Castori, Marco; Castro, Ariel F; Castro-Caldas, Margarida; Castro-Hernandez, Javier; Castro-Obregon, Susana; Catz, Sergio D; Cavadas, Claudia; Cavaliere, Federica; Cavallini, Gabriella; Cavinato, Maria; Cayuela, Maria L; Cebollada Rica, Paula; Cecarini, Valentina; Cecconi, Francesco; Cechowska-Pasko, Marzanna; Cenci, Simone; Ceperuelo-Mallafré, Victòria; Cerqueira, João J; Cerutti, Janete M; Cervia, Davide; Cetintas, Vildan Bozok; Cetrullo, Silvia; Chae, Han-Jung; Chagin, Andrei S; Chai, Chee-Yin; Chakrabarti, Gopal; Chakrabarti, Oishee; Chakraborty, Tapas; Chakraborty, Trinad; Chami, Mounia; Chamilos, Georgios; Chan, David W; Chan, Edmond Y W; Chan, Edward D; Chan, H Y Edwin; Chan, Helen H; Chan, Hung; Chan, Matthew T V; Chan, Yau Sang; Chandra, Partha K; Chang, Chih-Peng; Chang, Chunmei; Chang, Hao-Chun; Chang, Kai; Chao, Jie; Chapman, Tracey; Charlet-Berguerand, Nicolas; Chatterjee, Samrat; Chaube, Shail K; Chaudhary, Anu; Chauhan, Santosh; Chaum, Edward; Checler, Frédéric; Cheetham, Michael E; Chen, Chang-Shi; Chen, Guang-Chao; Chen, Jian-Fu; Chen, Liam L; Chen, Leilei; Chen, Lin; Chen, Mingliang; Chen, Mu-Kuan; Chen, Ning; Chen, Quan; Chen, Ruey-Hwa; Chen, Shi; Chen, Wei; Chen, Weiqiang; Chen, Xin-Ming; Chen, Xiong-Wen; Chen, Xu; Chen, Yan; Chen, Ye-Guang; Chen, Yingyu; Chen, Yongqiang; Chen, Yu-Jen; Chen, Yue-Qin; Chen, Zhefan Stephen; Chen, Zhi; Chen, Zhi-Hua; Chen, Zhijian J; Chen, Zhixiang; Cheng, Hanhua; Cheng, Jun; Cheng, Shi-Yuan; Cheng, Wei; Cheng, Xiaodong; Cheng, Xiu-Tang; Cheng, Yiyun; Cheng, Zhiyong; Chen, Zhong; Cheong, Heesun; Cheong, Jit Kong; Chernyak, Boris V; Cherry, Sara; Cheung, Chi Fai Randy; Cheung, Chun Hei Antonio; Cheung, King-Ho; Chevet, Eric; Chi, Richard J; Chiang, Alan Kwok Shing; Chiaradonna, Ferdinando; Chiarelli, Roberto; Chiariello, Mario; Chica, Nathalia; Chiocca, Susanna; Chiong, Mario; Chiou, Shih-Hwa; Chiramel, Abhilash I; Chiurchiù, Valerio; Cho, Dong-Hyung; Choe, Seong-Kyu; Choi, Augustine M K; Choi, Mary E; Choudhury, Kamalika Roy; Chow, Norman S; Chu, Charleen T; Chua, Jason P; Chua, John Jia En; Chung, Hyewon; Chung, Kin Pan; Chung, Seockhoon; Chung, So-Hyang; Chung, Yuen-Li; Cianfanelli, Valentina; Ciechomska, Iwona A; Cifuentes, Mariana; Cinque, Laura; Cirak, Sebahattin; Cirone, Mara; Clague, Michael J; Clarke, Robert; Clementi, Emilio; Coccia, Eliana M; Codogno, Patrice; Cohen, Ehud; Cohen, Mickael M; Colasanti, Tania; Colasuonno, Fiorella; Colbert, Robert A; Colell, Anna; Čolić, Miodrag; Coll, Nuria S; Collins, Mark O; Colombo, María I; Colón-Ramos, Daniel A; Combaret, Lydie; Comincini, Sergio; Cominetti, Márcia R; Consiglio, Antonella; Conte, Andrea; Conti, Fabrizio; Contu, Viorica Raluca; Cookson, Mark R; Coombs, Kevin M; Coppens, Isabelle; Corasaniti, Maria Tiziana; Corkery, Dale P; Cordes, Nils; Cortese, Katia; Costa, Maria do Carmo; Costantino, Sarah; Costelli, Paola; Coto-Montes, Ana; Crack, Peter J; Crespo, Jose L; Criollo, Alfredo; Crippa, Valeria; Cristofani, Riccardo; Csizmadia, Tamas; Cuadrado, Antonio; Cui, Bing; Cui, Jun; Cui, Yixian; Cui, Yong; Culetto, Emmanuel; Cumino, Andrea C; Cybulsky, Andrey V; Czaja, Mark J; Czuczwar, Stanislaw J; D'Adamo, Stefania; D'Amelio, Marcello; D'Arcangelo, Daniela; D'Lugos, Andrew C; D'Orazi, Gabriella; da Silva, James A; Dafsari, Hormos Salimi; Dagda, Ruben K; Dagdas, Yasin; Daglia, Maria; Dai, Xiaoxia; Dai, Yun; Dai, Yuyuan; Dal Col, Jessica; Dalhaimer, Paul; Dalla Valle, Luisa; Dallenga, Tobias; Dalmasso, Guillaume; Damme, Markus; Dando, Ilaria; Dantuma, Nico P; Darling, April L; Das, Hiranmoy; Dasarathy, Srinivasan; Dasari, Santosh K; Dash, Srikanta; Daumke, Oliver; Dauphinee, Adrian N; Davies, Jeffrey S; Dávila, Valeria A; Davis, Roger J; Davis, Tanja; Dayalan Naidu, Sharadha; De Amicis, Francesca; De Bosscher, Karolien; De Felice, Francesca; De Franceschi, Lucia; De Leonibus, Chiara; de Mattos Barbosa, Mayara G; De Meyer, Guido R Y; De Milito, Angelo; De Nunzio, Cosimo; De Palma, Clara; De Santi, Mauro; De Virgilio, Claudio; De Zio, Daniela; Debnath, Jayanta; DeBosch, Brian J; Decuypere, Jean-Paul; Deehan, Mark A; Deflorian, Gianluca; DeGregori, James; Dehay, Benjamin; Del Rio, Gabriel; Delaney, Joe R; Delbridge, Lea M D; Delorme-Axford, Elizabeth; Delpino, M Victoria; Demarchi, Francesca; Dembitz, Vilma; Demers, Nicholas D; Deng, Hongbin; Deng, Zhiqiang; Dengjel, Joern; Dent, Paul; Denton, Donna; DePamphilis, Melvin L; Der, Channing J; Deretic, Vojo; Descoteaux, Albert; Devis, Laura; Devkota, Sushil; Devuyst, Olivier; Dewson, Grant; Dharmasivam, Mahendiran; Dhiman, Rohan; di Bernardo, Diego; Di Cristina, Manlio; Di Domenico, Fabio; Di Fazio, Pietro; Di Fonzo, Alessio; Di Guardo, Giovanni; Di Guglielmo, Gianni M; Di Leo, Luca; Di Malta, Chiara; Di Nardo, Alessia; Di Rienzo, Martina; Di Sano, Federica; Diallinas, George; Diao, Jiajie; Diaz-Araya, Guillermo; Díaz-Laviada, Inés; Dickinson, Jared M; Diederich, Marc; Dieudé, Mélanie; Dikic, Ivan; Ding, Shiping; Ding, Wen-Xing; Dini, Luciana; Dinić, Jelena; Dinic, Miroslav; Dinkova-Kostova, Albena T; Dionne, Marc S; Distler, Jörg H W; Diwan, Abhinav; Dixon, Ian M C; Djavaheri-Mergny, Mojgan; Dobrinski, Ina; Dobrovinskaya, Oxana; Dobrowolski, Radek; Dobson, Renwick C J; Đokić, Jelena; Dokmeci Emre, Serap; Donadelli, Massimo; Dong, Bo; Dong, Xiaonan; Dong, Zhiwu; Dorn Ii, Gerald W; Dotsch, Volker; Dou, Huan; Dou, Juan; Dowaidar, Moataz; Dridi, Sami; Drucker, Liat; Du, Ailian; Du, Caigan; Du, Guangwei; Du, Hai-Ning; Du, Li-Lin; du Toit, André; Duan, Shao-Bin; Duan, Xiaoqiong; Duarte, Sónia P; Dubrovska, Anna; Dunlop, Elaine A; Dupont, Nicolas; Durán, Raúl V; Dwarakanath, Bilikere S; Dyshlovoy, Sergey A; Ebrahimi-Fakhari, Darius; Eckhart, Leopold; Edelstein, Charles L; Efferth, Thomas; Eftekharpour, Eftekhar; Eichinger, Ludwig; Eid, Nabil; Eisenberg, Tobias; Eissa, N Tony; Eissa, Sanaa; Ejarque, Miriam; El Andaloussi, Abdeljabar; El-Hage, Nazira; El-Naggar, Shahenda; Eleuteri, Anna Maria; El-Shafey, Eman S; Elgendy, Mohamed; Eliopoulos, Aristides G; Elizalde, María M; Elks, Philip M; Elsasser, Hans-Peter; Elsherbiny, Eslam S; Emerling, Brooke M; Emre, N C Tolga; Eng, Christina H; Engedal, Nikolai; Engelbrecht, Anna-Mart; Engelsen, Agnete S T; Enserink, Jorrit M; Escalante, Ricardo; Esclatine, Audrey; Escobar-Henriques, Mafalda; Eskelinen, Eeva-Liisa; Espert, Lucile; Eusebio, Makandjou-Ola; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Facchiano, Francesco; Fadeel, Bengt; Fader, Claudio; Faesen, Alex C; Fairlie, W Douglas; Falcó, Alberto; Falkenburger, Bjorn H; Fan, Daping; Fan, Jie; Fan, Yanbo; Fang, Evandro F; Fang, Yanshan; Fang, Yognqi; Fanto, Manolis; Farfel-Becker, Tamar; Faure, Mathias; Fazeli, Gholamreza; Fedele, Anthony O; Feldman, Arthur M; Feng, Du; Feng, Jiachun; Feng, Lifeng; Feng, Yibin; Feng, Yuchen; Feng, Wei; Fenz Araujo, Thais; Ferguson, Thomas A; Fernández, Álvaro F; Fernandez-Checa, Jose C; Fernández-Veledo, Sonia; Fernie, Alisdair R; Ferrante, Anthony W; Ferraresi, Alessandra; Ferrari, Merari F; Ferreira, Julio C B; Ferro-Novick, Susan; Figueras, Antonio; Filadi, Riccardo; Filigheddu, Nicoletta; Filippi-Chiela, Eduardo; Filomeni, Giuseppe; Fimia, Gian Maria; Fineschi, Vittorio; Finetti, Francesca; Finkbeiner, Steven; Fisher, Edward A; Fisher, Paul B; Flamigni, Flavio; Fliesler, Steven J; Flo, Trude H; Florance, Ida; Florey, Oliver; Florio, Tullio; Fodor, Erika; Follo, Carlo; Fon, Edward A; Forlino, Antonella; Fornai, Francesco; Fortini, Paola; Fracassi, Anna; Fraldi, Alessandro; Franco, Brunella; Franco, Rodrigo; Franconi, Flavia; Frankel, Lisa B; Friedman, Scott L; Fröhlich, Leopold F; Frühbeck, Gema; Fuentes, Jose M; Fujiki, Yukio; Fujita, Naonobu; Fujiwara, Yuuki; Fukuda, Mitsunori; Fulda, Simone; Furic, Luc; Furuya, Norihiko; Fusco, Carmela; Gack, Michaela U; Gaffke, Lidia; Galadari, Sehamuddin; Galasso, Alessia; Galindo, Maria F; Gallolu Kankanamalage, Sachith; Galluzzi, Lorenzo; Galy, Vincent; Gammoh, Noor; Gan, Boyi; Ganley, Ian G; Gao, Feng; Gao, Hui; Gao, Minghui; Gao, Ping; Gao, Shou-Jiang; Gao, Wentao; Gao, Xiaobo; Garcera, Ana; Garcia, Maria Noé; Garcia, Verónica E; García-Del Portillo, Francisco; Garcia-Escudero, Vega; Garcia-Garcia, Aracely; Garcia-Macia, Marina; García-Moreno, Diana; Garcia-Ruiz, Carmen; García-Sanz, Patricia; Garg, Abhishek D; Gargini, Ricardo; Garofalo, Tina; Garry, Robert F; Gassen, Nils C; Gatica, Damian; Ge, Liang; Ge, Wanzhong; Geiss-Friedlander, Ruth; Gelfi, Cecilia; Genschik, Pascal; Gentle, Ian E; Gerbino, Valeria; Gerhardt, Christoph; Germain, Kyla; Germain, Marc; Gewirtz, David A; Ghasemipour Afshar, Elham; Ghavami, Saeid; Ghigo, Alessandra; Ghosh, Manosij; Giamas, Georgios; Giampietri, Claudia; Giatromanolaki, Alexandra; Gibson, Gary E; Gibson, Spencer B; Ginet, Vanessa; Giniger, Edward; Giorgi, Carlotta; Girao, Henrique; Girardin, Stephen E; Giridharan, Mridhula; Giuliano, Sandy; Giulivi, Cecilia; Giuriato, Sylvie; Giustiniani, Julien; Gluschko, Alexander; Goder, Veit; Goginashvili, Alexander; Golab, Jakub; Goldstone, David C; Golebiewska, Anna; Gomes, Luciana R; Gomez, Rodrigo; Gómez-Sánchez, Rubén; Gomez-Puerto, Maria Catalina; Gomez-Sintes, Raquel; Gong, Qingqiu; Goni, Felix M; González-Gallego, Javier; Gonzalez-Hernandez, Tomas; Gonzalez-Polo, Rosa A; Gonzalez-Reyes, Jose A; González-Rodríguez, Patricia; Goping, Ing Swie; Gorbatyuk, Marina S; Gorbunov, Nikolai V; Görgülü, Kıvanç; Gorojod, Roxana M; Gorski, Sharon M; Goruppi, Sandro; Gotor, Cecilia; Gottlieb, Roberta A; Gozes, Illana; Gozuacik, Devrim; Graef, Martin; Gräler, Markus H; Granatiero, Veronica; Grasso, Daniel; Gray, Joshua P; Green, Douglas R; Greenhough, Alexander; Gregory, Stephen L; Griffin, Edward F; Grinstaff, Mark W; Gros, Frederic; Grose, Charles; Gross, Angelina S; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Gu, Xueyan; Guan, Jun-Lin; Guardia, Carlos M; Guda, Kishore; Guerra, Flora; Guerri, Consuelo; Guha, Prasun; Guillén, Carlos; Gujar, Shashi; Gukovskaya, Anna; Gukovsky, Ilya; Gunst, Jan; Günther, Andreas; Guntur, Anyonya R; Guo, Chuanyong; Guo, Chun; Guo, Hongqing; Guo, Lian-Wang; Guo, Ming; Gupta, Pawan; Gupta, Shashi Kumar; Gupta, Swapnil; Gupta, Veer Bala; Gupta, Vivek; Gustafsson, Asa B; Gutterman, David D; H B, Ranjitha; Haapasalo, Annakaisa; Haber, James E; Hać, Aleksandra; Hadano, Shinji; Hafrén, Anders J; Haidar, Mansour; Hall, Belinda S; Halldén, Gunnel; Hamacher-Brady, Anne; Hamann, Andrea; Hamasaki, Maho; Han, Weidong; Hansen, Malene; Hanson, Phyllis I; Hao, Zijian; Harada, Masaru; Harhaji-Trajkovic, Ljubica; Hariharan, Nirmala; Haroon, Nigil; Harris, James; Hasegawa, Takafumi; Hasima Nagoor, Noor; Haspel, Jeffrey A; Haucke, Volker; Hawkins, Wayne D; Hay, Bruce A; Haynes, Cole M; Hayrabedyan, Soren B; Hays, Thomas S; He, Congcong; He, Qin; He, Rong-Rong; He, You-Wen; He, Yu-Ying; Heakal, Yasser; Heberle, Alexander M; Hejtmancik, J Fielding; Helgason, Gudmundur Vignir; Henkel, Vanessa; Herb, Marc; Hergovich, Alexander; Herman-Antosiewicz, Anna; Hernández, Agustín; Hernandez, Carlos; Hernandez-Diaz, Sergio; Hernandez-Gea, Virginia; Herpin, Amaury; Herreros, Judit; Hervás, Javier H; Hesselson, Daniel; Hetz, Claudio; Heussler, Volker T; Higuchi, Yujiro; Hilfiker, Sabine; Hill, Joseph A; Hlavacek, William S; Ho, Emmanuel A; Ho, Idy H T; Ho, Philip Wing-Lok; Ho, Shu-Leong; Ho, Wan Yun; Hobbs, G Aaron; Hochstrasser, Mark; Hoet, Peter H M; Hofius, Daniel; Hofman, Paul; Höhn, Annika; Holmberg, Carina I; Hombrebueno, Jose R; Yi-Ren Hong, Chang-Won Hong; Hooper, Lora V; Hoppe, Thorsten; Horos, Rastislav; Hoshida, Yujin; Hsin, I-Lun; Hsu, Hsin-Yun; Hu, Bing; Hu, Dong; Hu, Li-Fang; Hu, Ming Chang; Hu, Ronggui; Hu, Wei; Hu, Yu-Chen; Hu, Zhuo-Wei; Hua, Fang; Hua, Jinlian; Hua, Yingqi; Huan, Chongmin; Huang, Canhua; Huang, Chuanshu; Huang, Chuanxin; Huang, Chunling; Huang, Haishan; Huang, Kun; Huang, Michael L H; Huang, Rui; Huang, Shan; Huang, Tianzhi; Huang, Xing; Huang, Yuxiang Jack; Huber, Tobias B; Hubert, Virginie; Hubner, Christian A; Hughes, Stephanie M; Hughes, William E; Humbert, Magali; Hummer, Gerhard; Hurley, James H; Hussain, Sabah; Hussain, Salik; Hussey, Patrick J; Hutabarat, Martina; Hwang, Hui-Yun; Hwang, Seungmin; Ieni, Antonio; Ikeda, Fumiyo; Imagawa, Yusuke; Imai, Yuzuru; Imbriano, Carol; Imoto, Masaya; Inman, Denise M; Inoki, Ken; Iovanna, Juan; Iozzo, Renato V; Ippolito, Giuseppe; Irazoqui, Javier E; Iribarren, Pablo; Ishaq, Mohd; Ishikawa, Makoto; Ishimwe, Nestor; Isidoro, Ciro; Ismail, Nahed; Issazadeh-Navikas, Shohreh; Itakura, Eisuke; Ito, Daisuke; Ivankovic, Davor; Ivanova, Saška; Iyer, Anand Krishnan V; Izquierdo, José M; Izumi, Masanori; Jäättelä, Marja; Jabir, Majid Sakhi; Jackson, William T; Jacobo-Herrera, Nadia; Jacomin, Anne-Claire; Jacquin, Elise; Jadiya, Pooja; Jaeschke, Hartmut; Jagannath, Chinnaswamy; Jakobi, Arjen J; Jakobsson, Johan; Janji, Bassam; Jansen-Dürr, Pidder; Jansson, Patric J; Jantsch, Jonathan; Januszewski, Sławomir; Jassey, Alagie; Jean, Steve; Jeltsch-David, Hélène; Jendelova, Pavla; Jenny, Andreas; Jensen, Thomas E; Jessen, Niels; Jewell, Jenna L; Ji, Jing; Jia, Lijun; Jia, Rui; Jiang, Liwen; Jiang, Qing; Jiang, Richeng; Jiang, Teng; Jiang, Xuejun; Jiang, Yu; Jimenez-Sanchez, Maria; Jin, Eun-Jung; Jin, Fengyan; Jin, Hongchuan; Jin, Li; Jin, Luqi; Jin, Meiyan; Jin, Si; Jo, Eun-Kyeong; Joffre, Carine; Johansen, Terje; Johnson, Gail V W; Johnston, Simon A; Jokitalo, Eija; Jolly, Mohit Kumar; Joosten, Leo A B; Jordan, Joaquin; Joseph, Bertrand; Ju, Dianwen; Ju, Jeong-Sun; Ju, Jingfang; Juárez, Esmeralda; Judith, Delphine; Juhász, Gábor; Jun, Youngsoo; Jung, Chang Hwa; Jung, Sung-Chul; Jung, Yong Keun; Jungbluth, Heinz; Jungverdorben, Johannes; Just, Steffen; Kaarniranta, Kai; Kaasik, Allen; Kabuta, Tomohiro; Kaganovich, Daniel; Kahana, Alon; Kain, Renate; Kajimura, Shinjo; Kalamvoki, Maria; Kalia, Manjula; Kalinowski, Danuta S; Kaludercic, Nina; Kalvari, Ioanna; Kaminska, Joanna; Kaminskyy, Vitaliy O; Kanamori, Hiromitsu; Kanasaki, Keizo; Kang, Chanhee; Kang, Rui; Kang, Sang Sun; Kaniyappan, Senthilvelrajan; Kanki, Tomotake; Kanneganti, Thirumala-Devi; Kanthasamy, Anumantha G; Kanthasamy, Arthi; Kantorow, Marc; Kapuy, Orsolya; Karamouzis, Michalis V; Karim, Md Razaul; Karmakar, Parimal; Katare, Rajesh G; Kato, Masaru; Kaufmann, Stefan H E; Kauppinen, Anu; Kaushal, Gur P; Kaushik, Susmita; Kawasaki, Kiyoshi; Kazan, Kemal; Ke, Po-Yuan; Keating, Damien J; Keber, Ursula; Kehrl, John H; Keller, Kate E; Keller, Christian W; Kemper, Jongsook Kim; Kenific, Candia M; Kepp, Oliver; Kermorgant, Stephanie; Kern, Andreas; Ketteler, Robin; Keulers, Tom G; Khalfin, Boris; Khalil, Hany; Khambu, Bilon; Khan, Shahid Y; Khandelwal, Vinoth Kumar Megraj; Khandia, Rekha; Kho, Widuri; Khobrekar, Noopur V; Khuansuwan, Sataree; Khundadze, Mukhran; Killackey, Samuel A; Kim, Dasol; Kim, Deok Ryong; Kim, Do-Hyung; Kim, Dong-Eun; Kim, Eun Young; Kim, Eun-Kyoung; Kim, Hak-Rim; Kim, Hee-Sik; Kim, Jeong Hun; Kim, Jin Kyung; Kim, Jin-Hoi; Kim, Joungmok; Kim, Ju Hwan; Kim, Keun Il; Kim, Peter K; Kim, Seong-Jun; Kimball, Scot R; Kimchi, Adi; Kimmelman, Alec C; Kimura, Tomonori; King, Matthew A; Kinghorn, Kerri J; Kinsey, Conan G; Kirkin, Vladimir; Kirshenbaum, Lorrie A; Kiselev, Sergey L; Kishi, Shuji; Kitamoto, Katsuhiko; Kitaoka, Yasushi; Kitazato, Kaio; Kitsis, Richard N; Kittler, Josef T; Kjaerulff, Ole; Klein, Peter S; Klopstock, Thomas; Klucken, Jochen; Knævelsrud, Helene; Knorr, Roland L; Ko, Ben C B; Ko, Fred; Ko, Jiunn-Liang; Kobayashi, Hotaka; Kobayashi, Satoru; Koch, Ina; Koch, Jan C; Koenig, Ulrich; Kögel, Donat; Koh, Young Ho; Koike, Masato; Kohlwein, Sepp D; Kocaturk, Nur M; Komatsu, Masaaki; König, Jeannette; Kono, Toru; Kopp, Benjamin T; Korcsmaros, Tamas; Korkmaz, Gözde; Korolchuk, Viktor I; Korsnes, Mónica Suárez; Koskela, Ali; Kota, Janaiah; Kotake, Yaichiro; Kotler, Monica L; Kou, Yanjun; Koukourakis, Michael I; Koustas, Evangelos; Kovacs, Attila L; Kovács, Tibor; Koya, Daisuke; Kozako, Tomohiro; Kraft, Claudine; Krainc, Dimitri; Krämer, Helmut; Krasnodembskaya, Anna D; Kretz-Remy, Carole; Kroemer, Guido; Ktistakis, Nicholas T; Kuchitsu, Kazuyuki; Kuenen, Sabine; Kuerschner, Lars; Kukar, Thomas; Kumar, Ajay; Kumar, Ashok; Kumar, Deepak; Kumar, Dhiraj; Kumar, Sharad; Kume, Shinji; Kumsta, Caroline; Kundu, Chanakya N; Kundu, Mondira; Kunnumakkara, Ajaikumar B; Kurgan, Lukasz; Kutateladze, Tatiana G; Kutlu, Ozlem; Kwak, SeongAe; Kwon, Ho Jeong; Kwon, Taeg Kyu; Kwon, Yong Tae; Kyrmizi, Irene; La Spada, Albert; Labonté, Patrick; Ladoire, Sylvain; Laface, Ilaria; Lafont, Frank; Lagace, Diane C; Lahiri, Vikramjit; Lai, Zhibing; Laird, Angela S; Lakkaraju, Aparna; Lamark, Trond; Lan, Sheng-Hui; Landajuela, Ane; Lane, Darius J R; Lane, Jon D; Lang, Charles H; Lange, Carsten; Langel, Ülo; Langer, Rupert; Lapaquette, Pierre; Laporte, Jocelyn; LaRusso, Nicholas F; Lastres-Becker, Isabel; Lau, Wilson Chun Yu; Laurie, Gordon W; Lavandero, Sergio; Law, Betty Yuen Kwan; Law, Helen Ka-Wai; Layfield, Rob; Le, Weidong; Le Stunff, Herve; Leary, Alexandre Y; Lebrun, Jean-Jacques; Leck, Lionel Y W; Leduc-Gaudet, Jean-Philippe; Lee, Changwook; Lee, Chung-Pei; Lee, Da-Hye; Lee, Edward B; Lee, Erinna F; Lee, Gyun Min; Lee, He-Jin; Lee, Heung Kyu; Lee, Jae Man; Lee, Jason S; Lee, Jin-A; Lee, Joo-Yong; Lee, Jun Hee; Lee, Michael; Lee, Min Goo; Lee, Min Jae; Lee, Myung-Shik; Lee, Sang Yoon; Lee, Seung-Jae; Lee, Stella Y; Lee, Sung Bae; Lee, Won Hee; Lee, Ying-Ray; Lee, Yong-Ho; Lee, Youngil; Lefebvre, Christophe; Legouis, Renaud; Lei, Yu L; Lei, Yuchen; Leikin, Sergey; Leitinger, Gerd; Lemus, Leticia; Leng, Shuilong; Lenoir, Olivia; Lenz, Guido; Lenz, Heinz Josef; Lenzi, Paola; León, Yolanda; Leopoldino, Andréia M; Leschczyk, Christoph; Leskelä, Stina; Letellier, Elisabeth; Leung, Chi-Ting; Leung, Po Sing; Leventhal, Jeremy S; Levine, Beth; Lewis, Patrick A; Ley, Klaus; Li, Bin; Li, Da-Qiang; Li, Jianming; Li, Jing; Li, Jiong; Li, Ke; Li, Liwu; Li, Mei; Li, Min; Li, Min; Li, Ming; Li, Mingchuan; Li, Pin-Lan; Li, Ming-Qing; Li, Qing; Li, Sheng; Li, Tiangang; Li, Wei; Li, Wenming; Li, Xue; Li, Yi-Ping; Li, Yuan; Li, Zhiqiang; Li, Zhiyong; Li, Zhiyuan; Lian, Jiqin; Liang, Chengyu; Liang, Qiangrong; Liang, Weicheng; Liang, Yongheng; Liang, YongTian; Liao, Guanghong; Liao, Lujian; Liao, Mingzhi; Liao, Yung-Feng; Librizzi, Mariangela; Lie, Pearl P Y; Lilly, Mary A; Lim, Hyunjung J; Lima, Thania R R; Limana, Federica; Lin, Chao; Lin, Chih-Wen; Lin, Dar-Shong; Lin, Fu-Cheng; Lin, Jiandie D; Lin, Kurt M; Lin, Kwang-Huei; Lin, Liang-Tzung; Lin, Pei-Hui; Lin, Qiong; Lin, Shaofeng; Lin, Su-Ju; Lin, Wenyu; Lin, Xueying; Lin, Yao-Xin; Lin, Yee-Shin; Linden, Rafael; Lindner, Paula; Ling, Shuo-Chien; Lingor, Paul; Linnemann, Amelia K; Liou, Yih-Cherng; Lipinski, Marta M; Lipovšek, Saška; Lira, Vitor A; Lisiak, Natalia; Liton, Paloma B; Liu, Chao; Liu, Ching-Hsuan; Liu, Chun-Feng; Liu, Cui Hua; Liu, Fang; Liu, Hao; Liu, Hsiao-Sheng; Liu, Hua-Feng; Liu, Huifang; Liu, Jia; Liu, Jing; Liu, Julia; Liu, Leyuan; Liu, Longhua; Liu, Meilian; Liu, Qin; Liu, Wei; Liu, Wende; Liu, Xiao-Hong; Liu, Xiaodong; Liu, Xingguo; Liu, Xu; Liu, Xuedong; Liu, Yanfen; Liu, Yang; Liu, Yang; Liu, Yueyang; Liu, Yule; Livingston, J Andrew; Lizard, Gerard; Lizcano, Jose M; Ljubojevic-Holzer, Senka; LLeonart, Matilde E; Llobet-Navàs, David; Llorente, Alicia; Lo, Chih Hung; Lobato-Márquez, Damián; Long, Qi; Long, Yun Chau; Loos, Ben; Loos, Julia A; López, Manuela G; López-Doménech, Guillermo; López-Guerrero, José Antonio; López-Jiménez, Ana T; López-Pérez, Óscar; López-Valero, Israel; Lorenowicz, Magdalena J; Lorente, Mar; Lorincz, Peter; Lossi, Laura; Lotersztajn, Sophie; Lovat, Penny E; Lovell, Jonathan F; Lovy, Alenka; Lőw, Péter; Lu, Guang; Lu, Haocheng; Lu, Jia-Hong; Lu, Jin-Jian; Lu, Mengji; Lu, Shuyan; Luciani, Alessandro; Lucocq, John M; Ludovico, Paula; Luftig, Micah A; Luhr, Morten; Luis-Ravelo, Diego; Lum, Julian J; Luna-Dulcey, Liany; Lund, Anders H; Lund, Viktor K; Lünemann, Jan D; Lüningschrör, Patrick; Luo, Honglin; Luo, Rongcan; Luo, Shouqing; Luo, Zhi; Luparello, Claudio; Lüscher, Bernhard; Luu, Luan; Lyakhovich, Alex; Lyamzaev, Konstantin G; Lystad, Alf Håkon; Lytvynchuk, Lyubomyr; Ma, Alvin C; Ma, Changle; Ma, Mengxiao; Ma, Ning-Fang; Ma, Quan-Hong; Ma, Xinliang; Ma, Yueyun; Ma, Zhenyi; MacDougald, Ormond A; Macian, Fernando; MacIntosh, Gustavo C; MacKeigan, Jeffrey P; Macleod, Kay F; Maday, Sandra; Madeo, Frank; Madesh, Muniswamy; Madl, Tobias; Madrigal-Matute, Julio; Maeda, Akiko; Maejima, Yasuhiro; Magarinos, Marta; Mahavadi, Poornima; Maiani, Emiliano; Maiese, Kenneth; Maiti, Panchanan; Maiuri, Maria Chiara; Majello, Barbara; Major, Michael B; Makareeva, Elena; Malik, Fayaz; Mallilankaraman, Karthik; Malorni, Walter; Maloyan, Alina; Mammadova, Najiba; Man, Gene Chi Wai; Manai, Federico; Mancias, Joseph D; Mandelkow, Eva-Maria; Mandell, Michael A; Manfredi, Angelo A; Manjili, Masoud H; Manjithaya, Ravi; Manque, Patricio; Manshian, Bella B; Manzano, Raquel; Manzoni, Claudia; Mao, Kai; Marchese, Cinzia; Marchetti, Sandrine; Marconi, Anna Maria; Marcucci, Fabrizio; Mardente, Stefania; Mareninova, Olga A; Margeta, Marta; Mari, Muriel; Marinelli, Sara; Marinelli, Oliviero; Mariño, Guillermo; Mariotto, Sofia; Marshall, Richard S; Marten, Mark R; Martens, Sascha; Martin, Alexandre P J; Martin, Katie R; Martin, Sara; Martin, Shaun; Martín-Segura, Adrián; Martín-Acebes, Miguel A; Martin-Burriel, Inmaculada; Martin-Rincon, Marcos; Martin-Sanz, Paloma; Martina, José A; Martinet, Wim; Martinez, Aitor; Martinez, Ana; Martinez, Jennifer; Martinez Velazquez, Moises; Martinez-Lopez, Nuria; Martinez-Vicente, Marta; Martins, Daniel O; Martins, Joilson O; Martins, Waleska K; Martins-Marques, Tania; Marzetti, Emanuele; Masaldan, Shashank; Masclaux-Daubresse, Celine; Mashek, Douglas G; Massa, Valentina; Massieu, Lourdes; Masson, Glenn R; Masuelli, Laura; Masyuk, Anatoliy I; Masyuk, Tetyana V; Matarrese, Paola; Matheu, Ander; Matoba, Satoaki; Matsuzaki, Sachiko; Mattar, Pamela; Matte, Alessandro; Mattoscio, Domenico; Mauriz, José L; Mauthe, Mario; Mauvezin, Caroline; Maverakis, Emanual; Maycotte, Paola; Mayer, Johanna; Mazzoccoli, Gianluigi; Mazzoni, Cristina; Mazzulli, Joseph R; McCarty, Nami; McDonald, Christine; McGill, Mitchell R; McKenna, Sharon L; McLaughlin, BethAnn; McLoughlin, Fionn; McNiven, Mark A; McWilliams, Thomas G; Mechta-Grigoriou, Fatima; Medeiros, Tania Catarina; Medina, Diego L; Megeney, Lynn A; Megyeri, Klara; Mehrpour, Maryam; Mehta, Jawahar L; Meijer, Alfred J; Meijer, Annemarie H; Mejlvang, Jakob; Meléndez, Alicia; Melk, Annette; Memisoglu, Gonen; Mendes, Alexandrina F; Meng, Delong; Meng, Fei; Meng, Tian; Menna-Barreto, Rubem; Menon, Manoj B; Mercer, Carol; Mercier, Anne E; Mergny, Jean-Louis; Merighi, Adalberto; Merkley, Seth D; Merla, Giuseppe; Meske, Volker; Mestre, Ana Cecilia; Metur, Shree Padma; Meyer, Christian; Meyer, Hemmo; Mi, Wenyi; Mialet-Perez, Jeanne; Miao, Junying; Micale, Lucia; Miki, Yasuo; Milan, Enrico; Milczarek, Małgorzata; Miller, Dana L; Miller, Samuel I; Miller, Silke; Millward, Steven W; Milosevic, Ira; Minina, Elena A; Mirzaei, Hamed; Mirzaei, Hamid Reza; Mirzaei, Mehdi; Mishra, Amit; Mishra, Nandita; Mishra, Paras Kumar; Misirkic Marjanovic, Maja; Misasi, Roberta; Misra, Amit; Misso, Gabriella; Mitchell, Claire; Mitou, Geraldine; Miura, Tetsuji; Miyamoto, Shigeki; Miyazaki, Makoto; Miyazaki, Mitsunori; Miyazaki, Taiga; Miyazawa, Keisuke; Mizushima, Noboru; Mogensen, Trine H; Mograbi, Baharia; Mohammadinejad, Reza; Mohamud, Yasir; Mohanty, Abhishek; Mohapatra, Sipra; Möhlmann, Torsten; Mohmmed, Asif; Moles, Anna; Moley, Kelle H; Molinari, Maurizio; Mollace, Vincenzo; Møller, Andreas Buch; Mollereau, Bertrand; Mollinedo, Faustino; Montagna, Costanza; Monteiro, Mervyn J; Montella, Andrea; Montes, L Ruth; Montico, Barbara; Mony, Vinod K; Monzio Compagnoni, Giacomo; Moore, Michael N; Moosavi, Mohammad A; Mora, Ana L; Mora, Marina; Morales-Alamo, David; Moratalla, Rosario; Moreira, Paula I; Morelli, Elena; Moreno, Sandra; Moreno-Blas, Daniel; Moresi, Viviana; Morga, Benjamin; Morgan, Alwena H; Morin, Fabrice; Morishita, Hideaki; Moritz, Orson L; Moriyama, Mariko; Moriyasu, Yuji; Morleo, Manuela; Morselli, Eugenia; Moruno-Manchon, Jose F; Moscat, Jorge; Mostowy, Serge; Motori, Elisa; Moura, Andrea Felinto; Moustaid-Moussa, Naima; Mrakovcic, Maria; Muciño-Hernández, Gabriel; Mukherjee, Anupam; Mukhopadhyay, Subhadip; Mulcahy Levy, Jean M; Mulero, Victoriano; Muller, Sylviane; Münch, Christian; Munjal, Ashok; Munoz-Canoves, Pura; Muñoz-Galdeano, Teresa; Münz, Christian; Murakawa, Tomokazu; Muratori, Claudia; Murphy, Brona M; Murphy, J Patrick; Murthy, Aditya; Myöhänen, Timo T; Mysorekar, Indira U; Mytych, Jennifer; Nabavi, Seyed Mohammad; Nabissi, Massimo; Nagy, Péter; Nah, Jihoon; Nahimana, Aimable; Nakagawa, Ichiro; Nakamura, Ken; Nakatogawa, Hitoshi; Nandi, Shyam S; Nanjundan, Meera; Nanni, Monica; Napolitano, Gennaro; Nardacci, Roberta; Narita, Masashi; Nassif, Melissa; Nathan, Ilana; Natsumeda, Manabu; Naude, Ryno J; Naumann, Christin; Naveiras, Olaia; Navid, Fatemeh; Nawrocki, Steffan T; Nazarko, Taras Y; Nazio, Francesca; Negoita, Florentina; Neill, Thomas; Neisch, Amanda L; Neri, Luca M; Netea, Mihai G; Neubert, Patrick; Neufeld, Thomas P; Neumann, Dietbert; Neutzner, Albert; Newton, Phillip T; Ney, Paul A; Nezis, Ioannis P; Ng, Charlene C W; Ng, Tzi Bun; Nguyen, Hang T T; Nguyen, Long T; Ni, Hong-Min; Ní Cheallaigh, Clíona; Ni, Zhenhong; Nicolao, M Celeste; Nicoli, Francesco; Nieto-Diaz, Manuel; Nilsson, Per; Ning, Shunbin; Niranjan, Rituraj; Nishimune, Hiroshi; Niso-Santano, Mireia; Nixon, Ralph A; Nobili, Annalisa; Nobrega, Clevio; Noda, Takeshi; Nogueira-Recalde, Uxía; Nolan, Trevor M; Nombela, Ivan; Novak, Ivana; 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In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
PMID: 33634751
ISSN: 1554-8635
CID: 4800842

Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease

Pensalfini, Anna; Kim, Seonil; Subbanna, Shivakumar; Bleiwas, Cynthia; Goulbourne, Chris N; Stavrides, Philip H; Jiang, Ying; Lee, Ju-Hyun; Darji, Sandipkumar; Pawlik, Monika; Huo, Chunfeng; Peddy, James; Berg, Martin J; Smiley, John F; Basavarajappa, Balapal S; Nixon, Ralph A
Neuronal endosomal dysfunction, the earliest known pathobiology specific to Alzheimer's disease (AD), is mediated by the aberrant activation of Rab5 triggered by APP-β secretase cleaved C-terminal fragment (APP-βCTF). To distinguish pathophysiological consequences specific to overactivated Rab5 itself, we activate Rab5 independently from APP-βCTF in the PA-Rab5 mouse model. We report that Rab5 overactivation alone recapitulates diverse prodromal and degenerative features of AD. Modest neuron-specific transgenic Rab5 expression inducing hyperactivation of Rab5 comparable to that in AD brain reproduces AD-related Rab5-endosomal enlargement and mistrafficking, hippocampal synaptic plasticity deficits via accelerated AMPAR endocytosis and dendritic spine loss, and tau hyperphosphorylation via activated glycogen synthase kinase-3β. Importantly, Rab5-mediated endosomal dysfunction induces progressive cholinergic neurodegeneration and impairs hippocampal-dependent memory. Aberrant neuronal Rab5-endosome signaling, therefore, drives a pathogenic cascade distinct from β-amyloid-related neurotoxicity, which includes prodromal and neurodegenerative features of AD, and suggests Rab5 overactivation as a potential therapeutic target.
PMID: 33238112
ISSN: 2211-1247
CID: 4680792

Neurofilaments: neurobiological foundations for biomarker applications

Gafson, Arie R; Barthélemy, Nicolas R; Bomont, Pascale; Carare, Roxana O; Durham, Heather D; Julien, Jean-Pierre; Kuhle, Jens; Leppert, David; Nixon, Ralph A; Weller, Roy O; Zetterberg, Henrik; Matthews, Paul M
Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration.
PMID: 32408345
ISSN: 1460-2156
CID: 4438212

The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases

Nixon, Ralph A
Lysosomes figure prominently in theories of aging as the proteolytic system most responsible for eliminating growing burdens of damaged proteins and organelles in aging neurons and other long lived cells. Newer evidence shows that diverse experimental measures known to extend lifespan in invertebrate aging models share the property of boosting lysosomal clearance of substrates through the autophagy pathway. Maintaining an optimal level of lysosome acidification is particularly crucial for these anti-aging effects. The exceptional dependence of neurons on fully functional lysosomes is reflected by the phenotypes seen in congenital lysosomal storage disorders, which commonly present as severe neurodevelopmental or neurodegenerative conditions even though lysosomal deficits are systemic. Similar connections are now being appreciated between risk for late age-onset neurodegenerative disorders and primary lysosomal deficits. In diseases such as Alzheimer's and Parkinson's, as in aging alone, primary lysosome dysfunction due to acidification impairment is emerging as a frequent theme, supported by the growing list of familial neurodegenerative disorders that involve primary vATPase dysfunction. The additional cellular roles played by intraluminal pH in sensing nutrient and stress and modulating cellular signaling have further expanded the possible ways that lysosomal pH dysregulation in aging and disease can disrupt neuronal function. Here, we consider the impact of cellular aging on lysosomes and how these changes may create the tipping point for disease emergence in major late-age onset neurodegenerative disorders.
PMID: 32416272
ISSN: 1878-1454
CID: 4438412

β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of ClC-7

Lee, Ju-Hyun; Wolfe, Devin M; Darji, Sandipkumar; McBrayer, Mary Kate; Colacurcio, Daniel J; Kumar, Asok; Stavrides, Philip; Mohan, Panaiyur S; Nixon, Ralph A
Lysosomal dysfunction is considered pathogenic in Alzheimer disease (AD). Loss of presenilin-1 (PSEN1) function causing AD impedes acidification via defective vacuolar ATPase (vATPase) V0a1 subunit delivery to lysosomes. We report that isoproterenol (ISO) and related β2-adrenergic agonists reacidify lysosomes in PSEN1 Knock out (KO) cells and fibroblasts from PSEN1 familial AD patients, which restores lysosomal proteolysis, calcium homeostasis, and normal autophagy flux. We identify a novel rescue mechanism involving Portein Kinase A (PKA)-mediated facilitation of chloride channel-7 (ClC-7) delivery to lysosomes which reverses markedly lowered chloride (Cl-) content in PSEN1 KO lysosomes. Notably, PSEN1 loss of function impedes Endoplasmic Reticulum (ER)-to-lysosome delivery of ClC-7. Transcriptomics of PSEN1-deficient cells reveals strongly downregulated ER-to-lysosome transport pathways and reversibility by ISO, thus accounting for lysosomal Cl- deficits that compound pH elevation due to deficient vATPase and its rescue by β2-adrenergic agonists. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β2-adrenergic regulation of ClC-7, which can potentially be modulated therapeutically.
PMID: 32105735
ISSN: 1089-8638
CID: 4394692

mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

Bordi, Matteo; Darji, Sandipkumar; Sato, Yutaka; Mellén, Marian; Berg, Martin J; Kumar, Asok; Jiang, Ying; Nixon, Ralph A
Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
PMID: 31332166
ISSN: 2041-4889
CID: 3987912