RRC ID 36033
Author Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, Dobrowolski R.
Title Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.
Journal Cell Rep
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.
Volume 14(9)
Pages 2166-2179
Published 2016-3-8
DOI 10.1016/j.celrep.2016.02.006
PII S2211-1247(16)30074-2
PMID 26923592
PMC PMC4793148
MeSH 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 / genetics* Presenilins / metabolism TOR Serine-Threonine Kinases / metabolism
IF 8.109
Times Cited 42
DNA material pGL4-phSESN2 (RDB07413)