@article{2689932f1e0e4c36b882fdae561c161f,
title = "Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency",
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.",
author = "Kavya Reddy and Cusack, {Corey L.} and Nnah, {Israel C.} and Khoosheh Khayati and Chaitali Saqcena and Huynh, {Tuong B.} and Noggle, {Scott A.} and Andrea Ballabio and Radek Dobrowolski",
note = "Funding Information: We thank Bart de Strooper (VIB Center for the Biology of Disease, KU Leuven) for providing the PS-deficient MEFs; David Sabatini and Kathleen Ottina (Whitehead Institute for Biomedical Research, MIT) for the Sesn1,2,3-FLAG; Hilmar Bading for the GCaMP6f/s-NLS; Douglas Kim for the GCaMP6s constructs; RIKEN Bioresource Center and DNA bank, which is participating in the National Bio-Resources Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, for the pGL4-phSESN2 construct; Chi Wei Lu and Zhiping Pang (Child Health Institute of New Jersey, Rutgers University) for their advice on iPSC culture; and Wilma Friedman, Haesun Kim (Rutgers University), and the members of our laboratory for their helpful comments. This work was supported by a grant from the NIH (R25GM096161 to I.C.N.) and by the International Alzheimer{\textquoteright}s Association (NIRG-305325 to R.D.). ",
year = "2016",
month = mar,
day = "8",
doi = "10.1016/j.celrep.2016.02.006",
language = "English (US)",
volume = "14",
pages = "2166--2179",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}