Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die

Hwang, Jee-YeonGertner, MichaelPontarelli, FabrizioCourt-Vazquez, BrendaBennett, Michael Vander LaanOfengeim, DimitryZukin, Ruth Suzanne2017-03-282017Hwang, Jee-Yeon, Michael Gertner, Fabrizio Pontarelli, Brenda Court-Vazquez, Michael Vander Laan Bennett, Dimitry Ofengeim, and Ruth Suzanne Zukin. 2017. “Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die.” Cell Death and Differentiation 24 (2): 317-329. doi:10.1038/cdd.2016.140. http://dx.doi.org/10.1038/cdd.2016.140.http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731638The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy. This is significant in that autophagy, a catabolic process downstream of mTORC1, promotes the formation of autophagosomes that capture and target cytoplasmic components to lysosomes. Inhibitors of the lysosomal (but not proteasomal) pathway rescued the ischemia-induced decrease in mTOR, consistent with degradation of mTOR via the autophagy/lysosomal pathway. Administration of the mTORC1 inhibitor rapamycin or acute knockdown of mTOR promotes autophagy and attenuates ischemia-induced neuronal death, indicating an inverse causal relation between mTOR, autophagy, and neuronal death. Our findings identify a novel and previously unappreciated mechanism by which mTOR self-regulates its own levels in hippocampal neurons in a clinically relevant model of ischemic stroke.en-USGlobal ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to dieJournal Article2017-03-2810.1038/cdd.2016.140