Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

Document Type

Article

Publication Date

3-8-2016

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.

Identifier

84960337720 (Scopus)

Publication Title

Cell Reports

External Full Text Location

https://doi.org/10.1016/j.celrep.2016.02.006

e-ISSN

22111247

PubMed ID

26923592

First Page

2166

Last Page

2179

Issue

9

Volume

14

Grant

NIRG-305325

Fund Ref

National Institutes of Health

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