The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice.
The molecular mechanisms leading to and responsible for age-related, 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 in vitro cultured induced pluripotent stem cell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation 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-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.
Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, New Jersey, USA.
Khoosheh
K
Khayati
Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, New Jersey, USA.
Henri
H
Antikainen
Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, New Jersey, USA.
Edward M
EM
Bonder
Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, New Jersey, USA.
Gregory F
GF
Weber
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Warren D
WD
Kruger
Department of Microbiology, Biochemistry, and Molecular Genetics, International Center for Public Health, Rutgers-New Jersey Medical School, Newark, New Jersey, USA.|Institute of Bioorganic Chemistry, Poznań, Poland; and.|Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland.
Hieronim
H
Jakubowski
Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, New Jersey, USA; r.dobrowolski@rutgers.edu.
Radek
R
Dobrowolski
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D006710:Homocysteine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
Alzheimer’s disease; lysosomal clearance; metabolism; signaling