Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

Kavya Reddy, Corey L. Cusack, Israel C. Nnah, Khoosheh Khayati, Chaitali Saqcena, Tuong B. Huynh, Scott A. Noggle, Andrea Ballabio, Radek Dobrowolski

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2166-2179
Number of pages14
JournalCell Reports
Volume14
Issue number9
DOIs
StatePublished - Mar 8 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Reddy, K., Cusack, C. L., Nnah, I. C., Khayati, K., Saqcena, C., Huynh, T. B., Noggle, S. A., Ballabio, A., & Dobrowolski, R. (2016). Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency. Cell Reports, 14(9), 2166-2179. https://doi.org/10.1016/j.celrep.2016.02.006