Cargando…

Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Reddy, Kavya, Cusack, Corey L., Nnah, Israel C., Khayati, Khoosheh, Saqcena, Chaitali, Huynh, Tuong B., Noggle, Scott A., Ballabio, Andrea, Dobrowolski, Radek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793148/
https://www.ncbi.nlm.nih.gov/pubmed/26923592
http://dx.doi.org/10.1016/j.celrep.2016.02.006
_version_ 1782421350229475328
author Reddy, Kavya
Cusack, Corey L.
Nnah, Israel C.
Khayati, Khoosheh
Saqcena, Chaitali
Huynh, Tuong B.
Noggle, Scott A.
Ballabio, Andrea
Dobrowolski, Radek
author_facet Reddy, Kavya
Cusack, Corey L.
Nnah, Israel C.
Khayati, Khoosheh
Saqcena, Chaitali
Huynh, Tuong B.
Noggle, Scott A.
Ballabio, Andrea
Dobrowolski, Radek
author_sort Reddy, Kavya
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4793148
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Cell Press
record_format MEDLINE/PubMed
spelling pubmed-47931482016-03-24 Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency Reddy, Kavya Cusack, Corey L. Nnah, Israel C. Khayati, Khoosheh Saqcena, Chaitali Huynh, Tuong B. Noggle, Scott A. Ballabio, Andrea Dobrowolski, Radek Cell Rep Article 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. Cell Press 2016-02-25 /pmc/articles/PMC4793148/ /pubmed/26923592 http://dx.doi.org/10.1016/j.celrep.2016.02.006 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Reddy, Kavya
Cusack, Corey L.
Nnah, Israel C.
Khayati, Khoosheh
Saqcena, Chaitali
Huynh, Tuong B.
Noggle, Scott A.
Ballabio, Andrea
Dobrowolski, Radek
Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title_full Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title_fullStr Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title_full_unstemmed Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title_short Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency
title_sort dysregulation of nutrient sensing and clearance in presenilin deficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793148/
https://www.ncbi.nlm.nih.gov/pubmed/26923592
http://dx.doi.org/10.1016/j.celrep.2016.02.006
work_keys_str_mv AT reddykavya dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT cusackcoreyl dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT nnahisraelc dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT khayatikhoosheh dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT saqcenachaitali dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT huynhtuongb dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT nogglescotta dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT ballabioandrea dysregulationofnutrientsensingandclearanceinpresenilindeficiency
AT dobrowolskiradek dysregulationofnutrientsensingandclearanceinpresenilindeficiency