mTOR Mysteries: Nuances and Questions About the Mechanistic Target of Rapamycin in Neurodegeneration

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.

Keywords: Alzheimer’s disease; Parkinson’s disease; antagonistic pleiotropy; autophagy; insulin/Akt; mTOR.

FIGURE 1

mTORC1 pathway and regulation. mTORC1 is activated by insulin. Insulin/Akt signaling inhibits TSC1/2, thereby permitting the activation of the GTP-binding protein, Rheb. Rheb is the proximal activator of mTORC1. AMPK inhibits mTORC1 activity through indirect and direct mechanisms, phosphorylating TSC1/2 and the Raptor regulatory component of mTORC1. (Other trophic factors and pathways beyond insulin/Akt and AMPK, not shown for simplicity, also regulate mTORC1). mTORC1 downstream targets include proteins involved the mRNA translation, 4E-BP1 and p70S6K1, and those involved in autophagy, such as the initiator of autophagy, ULK1, and the master regulator of lysosomal biogenesis, TFEB. By regulating the activity of these and other proteins, mTORC1 promotes protein synthesis, which is required for synaptogenesis, learning, and memory, but can also impair autophagy, leading to mitochondrial dysfunction and neurotoxic protein aggregation (Aβ, phospho-tau, α-synuclein, etc.). Black arrows and red lines respectively represent positive and negative regulation.

FIGURE 2

mTORC1 mysteries. Six nuances regarding mTORC1 in neurodegenerative disease. The questions and examples below each topic are illustrative, not comprehensive, of the literature covered in this review. Disease abbreviations: ALS, Amyotrophic Lateral Sclerosis; FTD, frontotemporal dementia; HD, Huntington’s disease; MS, multiple sclerosis; PD, Parkinson’s disease.