1. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.
- Author
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Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, and Dobrowolski R
- Subjects
- Alzheimer Disease metabolism, Amino Acids metabolism, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Brain metabolism, Brain pathology, Calcium metabolism, Cell Nucleus metabolism, Cells, Cultured, Gene Regulatory Networks, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Multiprotein Complexes metabolism, Nuclear Proteins metabolism, Nutritional Physiological Phenomena, Peroxidases, Presenilins metabolism, TOR Serine-Threonine Kinases metabolism, Presenilins genetics
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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