Impaired auto-lysosomal system, along with the consequential disruption of molecular trafficking and cellular signaling is strongly linked to neurodegeneration. Efficient (macro)autophagy is required to remove aggregated proteins and defective organelles, whose accumulation associates with a number of human diseases like AD, Parkinson disease, and amyotropic lateral sclerosis.
Autophagy is strictly dependent on lysosomal function that is driven by the nutritional status of the cell. Specifically, amino acids are sensed by lysosomes through a protein complex (vacuolar ATPase, Ragulator complex, and the Rag heterodimers A/B and C/D) that tethers the mechanistic target of Rapamycin complex 1 (mTORC1) to their membrane.
The small GTPase Rheb (Ras homolog enriched in brain) activates mTORC1 on lysosomal membranes if TSC1/2 (tuberous sclerosis 1/2 complex) is inactivated by growth factor signaling. Thus, mTORC1 activity is regulated by amino acid levels (as readily monitored by tethering of the complex to lysosomal membranes) and cellular signaling. Activity of mTORC1 has a direct effect on the biogenesis of lysosomes and autophagosomes through TFEB (transcription factor EB).
TFEB is regulated by mTORC1 and positively regulates the activity of the CLEAR (coordinated lysosomal expression and regulation) gene network encoding for lysosomal and autophagosomal genes. Under normal feeding conditions, active mTORC1 phosphorylates TFEB allowing it to remain in the cytoplasm. When cells starve, mTORC1 displaces from the lysosomal membranes, is no longer active, and is unable to phosphorylate TFEB that then translocates into the nucleus to directly bind to promoter elements containing the CLEAR sequence. This way, the mTORC1/TFEB pathway determines the activity of the auto-lysosomal system and the number of associated organelles. The mTOR kinase activity has been recently described as another risk factor for AD.
Now researchers 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.
http://www.cell.com/cell-reports/abstract/S2211-1247(16)30074-2
Altered mechanism for nutrient sensing in Alzheimer disease
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