Abstract
The mechanistic target of rapamycin protein complex, mTORC1, has received attention in recent years for its role in aging and neurodegenerative diseases, such as Alzheimer’s disease. Numerous excellent reviews have been written on the pathways and drug targeting of this keystone regulator of metabolism. However, none have specifically highlighted several important nuances of mTOR regulation as relates to neurodegeneration. Herein, we focus on six such nuances/open questions: (1) “Antagonistic pleiotropy” – Should we weigh the beneficial anabolic functions of mTORC1 against its harmful inhibition of autophagy? (2) “Early/late-stage specificity” – Does the relative importance of these neuroprotective/neurotoxic actions change as a disease progresses? (3) “Regional specificity” – Does mTOR signaling respond differently to the same interventions in different brain regions? (4) “Disease specificity” – Could the same intervention to inhibit mTORC1 help in one disease and cause harm in another disease? (5) “Personalized therapy” – Might genetically-informed personalized therapies that inhibit particular nodes in the mTORC1 regulatory network be more effective than generalized therapies? (6) “Lifestyle interventions” – Could specific diets, micronutrients, or exercise alter mTORC1 signaling to prevent or improve the progression neurodegenerative diseases? This manuscript is devoted to discussing recent research findings that offer insights into these gaps in the literature, with the aim of inspiring further inquiry.
Highlights
INTRODUCTIONExcessive inhibition of mechanistic target of rapamycin complex 1 (mTORC1) can impair learning and memory and permit neuronal death (Blundell et al, 2008; Belelovsky et al, 2009; Gafford et al, 2011; Jobim et al, 2012; Graber et al, 2013)
One potential molecular target of such therapies is the mechanistic target of rapamycin complex 1, a nutrient sensor and metabolic regulator heavily implicated in the process of aging (Sharp and Strong, 2010; Papadopoli et al, 2019; Heras-Sandoval et al, 2020)
Excessive inhibition of mechanistic target of rapamycin complex 1 (mTORC1) can impair learning and memory and permit neuronal death (Blundell et al, 2008; Belelovsky et al, 2009; Gafford et al, 2011; Jobim et al, 2012; Graber et al, 2013). Despite these potentially positive functions of mTORC1 signaling in the brain, far more attention has been paid to its negative regulation of autophagy, an intracellular recycling process essential to maintaining neuronal integrity and protecting against neurodegenerative diseases (Oddo, 2012; Sarkar, 2013; Heras-Sandoval et al, 2020). mTORC1 inhibits autophagy at multiple levels, including the inhibitory phosphorylation of Unc-51-like kinase 1 (ULK1) and transcription factor EB (TFEB), which respectively initiate autophagy and promote the lysosomal biogenesis required to break down the contents of autophagosomes (Kim et al, 2011; Napolitano et al, 2018)
Summary
Excessive inhibition of mTORC1 can impair learning and memory and permit neuronal death (Blundell et al, 2008; Belelovsky et al, 2009; Gafford et al, 2011; Jobim et al, 2012; Graber et al, 2013) Despite these potentially positive functions of mTORC1 signaling in the brain, far more attention has been paid to its negative regulation of autophagy, an intracellular recycling process essential to maintaining neuronal integrity and protecting against neurodegenerative diseases (Oddo, 2012; Sarkar, 2013; Heras-Sandoval et al, 2020). Given the knowledge that mTORC1 can inhibit apoptosis, and distinct possibility that there may be a point past which activation of autophagy is insufficient to improve disease course (Majumder et al, 2011), it’s worth questioning whether mTORC1 inhibition could be harmful in late-stage neurodegenerative disease
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