TY - JOUR
T1 - The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice
AU - Khayati, Khoosheh
AU - Antikainen, Henri
AU - Bonder, Edward M.
AU - Weber, Gregory F.
AU - Kruger, Warren D.
AU - Jakubowski, Hieronim
AU - Dobrowolski, Radek
N1 - Funding Information:
This work was supported by grants from the Polish National Science Center (2012/07/B/NZ7/01178, 2013/09/B/NZ5/02794, and 2013/11/B/NZ1/00091) and the Rutgers University-Newark Research Office and the New Jersey Brain Health Institute (to H.J. and R.D.). The authors thank Drs. Andrea Ballabio (TIGEM, Pozzuoli, Italy) for the CLEARLuciferase, David Sabatini (Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA, USA) for pRK5-HA GST RagC and Flag-Leucyl tRNA synthetase pRK5, Tamotsu Yoshimori (Osaka University, Osaka, Japan) for ptfLC3, and Shawn Ferguson (Yale School of Medicine, New Haven, CT, USA) for ptdTomato-N1-FLCN constructs, and the members of our laboratory for their helpful comments.
Publisher Copyright:
© FASEB.
PY - 2017/2
Y1 - 2017/2
N2 - Themolecularmechanisms leading to andresponsible for age-related, sporadic Alzheimer'sdisease (AD) remain largelyunknown. It iswelldocumented that aging patientswith elevated levels of the amino acidmetabolite homocysteine (Hcy) are at high risk of developing AD.We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including in vitro cultured induced pluripotent stemcell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation of the mechanistic target of rapamycincomplex 1 (mTORC1)activity, one of themajor kinases incells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl-tRNA-synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine β-synthase-deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including β-amyloid and phospho-Tau. Formation of these protein aggregates leads to AD-like 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.-Khayati, K., Antikainen, H., Bonder, E. M., Weber, G. F., Kruger, W. D., Jakubowski, H., Dobrowolski, R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice. FASEB J. 31, 598-609 (2017). www.fasebj.org.
AB - Themolecularmechanisms leading to andresponsible for age-related, sporadic Alzheimer'sdisease (AD) remain largelyunknown. It iswelldocumented that aging patientswith elevated levels of the amino acidmetabolite homocysteine (Hcy) are at high risk of developing AD.We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including in vitro cultured induced pluripotent stemcell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation of the mechanistic target of rapamycincomplex 1 (mTORC1)activity, one of themajor kinases incells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl-tRNA-synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine β-synthase-deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including β-amyloid and phospho-Tau. Formation of these protein aggregates leads to AD-like 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.-Khayati, K., Antikainen, H., Bonder, E. M., Weber, G. F., Kruger, W. D., Jakubowski, H., Dobrowolski, R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice. FASEB J. 31, 598-609 (2017). www.fasebj.org.
KW - Alzheimer's disease
KW - Lysosomal clearance
KW - Metabolism
KW - Signaling
UR - http://www.scopus.com/inward/record.url?scp=85011263014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011263014&partnerID=8YFLogxK
U2 - 10.1096/fj.201600915R
DO - 10.1096/fj.201600915R
M3 - Article
C2 - 28148781
AN - SCOPUS:85011263014
VL - 31
SP - 598
EP - 609
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 2
ER -