{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:47:34Z","timestamp":1791604054953,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,10,25]],"date-time":"2016-10-25T00:00:00Z","timestamp":1477353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The molecular mechanisms leading to and responsible for age\u2010related, sporadic Alzheimer's disease (AD) remain largely unknown. It is well documented that aging patients with elevated levels of the amino acid metabolite homocysteine (Hcy) are at high risk of developing AD. We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including\n                    <jats:italic>in vitro<\/jats:italic>\n                    cultured induced pluripotent stem cell\u2010derived forebrain neurons and\n                    <jats:italic>in vivo<\/jats:italic>\n                    neurons in mouse brains. Exposure to Hcy resulted in up\u2010regulation of the mechanistic target of rapamycin complex 1 (mTORC1) activity, one of the major kinases in cells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl\u2010tRNA\u2010synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine \u03b2\u2010synthase\u2010deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including \u03b2\u2010amyloid and phospho\u2010Tau. Formation of these protein aggregates leads to AD\u2010like neurodegeneration. This pathology can be prevented by inhibition of mTORC1 or by induction of autophagy. We conclude that an increase of intracellular Hcy levels predisposes neurons to develop abnormal protein aggregates, which are hallmarks of AD and its associated onset and pathophysiology with age.\u2014Khayati, K., Antikainen, H., Bonder, E. M., Weber, G.F., Kruger, W.D., Jakubowski, H., Dobrowolski, R. The aminoacidmetabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice. FASEB J. 31, 598\u2013609 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201600915r","type":"journal-article","created":{"date-parts":[[2016,10,26]],"date-time":"2016-10-26T00:08:57Z","timestamp":1477440537000},"page":"598-609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice"],"prefix":"10.1096","volume":"31","author":[{"given":"Khoosheh","family":"Khayati","sequence":"first","affiliation":[{"name":"Federated Department of Biological Sciences Rutgers University\/New Jersey Institute of Technology Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri","family":"Antikainen","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences Rutgers University\/New Jersey Institute of Technology Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Bonder","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences Rutgers University\/New Jersey Institute of Technology Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory F.","family":"Weber","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences Rutgers University\/New Jersey Institute of Technology Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren D.","family":"Kruger","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieronim","family":"Jakubowski","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics International Center for Public Health Rutgers\u2010New Jersey Medical School Newark New Jersey USA"},{"name":"Institute of Bioorganic Chemistry Pozna\u0144 Poland"},{"name":"Department of Biochemistry and Biotechnology University of Life Sciences Pozna\u0144 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radek","family":"Dobrowolski","sequence":"additional","affiliation":[{"name":"Federated Department of Biological Sciences Rutgers University\/New Jersey Institute of Technology Newark New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,10,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3244"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2748"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.01.021"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04723"},{"key":"e_1_2_8_6_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1009485107","article-title":"Genome\u2010wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease","volume":"107","author":"Lipinski M. 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