Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

Cell Rep. 2016 Mar 8;14(9):2166-2179. doi: 10.1016/j.celrep.2016.02.006. Epub 2016 Feb 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Amino Acids
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Multiprotein Complexes
  • Nuclear Proteins
  • Presenilins
  • Tcfeb protein, mouse
  • Peroxidases
  • sestrin 2 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Calcium