Abstract
SummaryAttenuated 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.
Highlights
Alzheimer disease (AD) is the most common neurodegenerative disorder of our time
Amino acids are sensed by lysosomes through a protein complex that tethers the mechanistic target of Rapamycin complex 1 to their membranes (Laplante and Sabatini, 2012; Nnah et al, 2015)
As mechanistic target of rapamycin complex 1 (mTORC1) has yet to be characterized in PS deficiency, we decided to determine the expression levels of proteins associated with the complex
Summary
Alzheimer disease (AD) is the most common neurodegenerative disorder of our time. Functional abnormalities of autophagosomes and lysosomes have been identified as some of the early pathological features in AD brains, preceding the hallmark deposits of amyloid and Tau tangles (Nixon and Yang, 2011). Enlargement of endosomal compartments containing amyloid precursor protein (APP) peptides (Takahashi et al, 2002), lysosomal deficits, and progressive accumulation of autophagic vacuoles are widely observed in AD human samples and corresponding mouse models (Cataldo et al, 1997; Nixon and Yang, 2011; Nixon et al, 2005). MTORC1 activity is regulated by amino acid levels (as readily monitored by tethering of the complex to lysosomal membranes) and cellular signaling. MTORC1 displaces from the lysosomal membranes, is no longer active, and is unable to phosphorylate TFEB that translocates into the nucleus to directly bind to promoter elements containing the CLEAR sequence (Settembre et al., 2166 Cell Reports 14, 2166–2179, March 8, 2016 a2016 The Authors (legend continued on page)
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