title: Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.
abstract: Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD.
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA.
authors.forename: Kavya
authors.initials: K
authors.lastname: Reddy
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Cusack
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA.
authors.forename: Israel C
authors.initials: IC
authors.lastname: Nnah
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA.
authors.forename: Khoosheh
authors.initials: K
authors.lastname: Khayati
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Saqcena
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA.
authors.forename: Tuong B
authors.initials: TB
authors.lastname: Huynh
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Noggle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, 80131 Naples, Italy; Medical Genetics, Department of Translational Medicine, Federico II University, 80131 Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Federated Department of Biological Sciences, Rutgers University/New Jersey Institute of Technology, Newark, NJ 07102, USA. Electronic address: r.dobrowolski@rutgers.edu.
authors.forename: Radek
authors.initials: R
authors.lastname: Dobrowolski
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009747:Nutritional Physiological Phenomena; D010544:Peroxidases; D053763:Presenilins / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000084622:Sestrins
chemical_list: D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002118:Calcium; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D053763:Presenilins; D058570:TOR Serine-Threonine Kinases; C484068:Tcfeb protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins