mTOR Signaling in Neurodegenerative Disorders

The mammalian or mechanistic target of rapamycin (mTOR) is a serine–threonine kinase that orchestrates cellular growth, metabolism and proteostasis. In the healthy brain, mTOR complexes 1 and 2 (mTORC1 and mTORC2) regulate synaptic plasticity, neuronal survival and energy homeostasis. Dysregulation of mTOR signalling is now recognised as a key driver in the pathogenesis of Alzheimer’s, Parkinson’s, Huntington’s and other neurodegenerative disorders. Overactive mTORC1 inhibits autophagy, leading to accumulation of misfolded proteins such as amyloid-β and hyperphosphorylated tau, while perturbations in mTORC2 can impair cytoskeletal dynamics and neuronal resilience. Moreover, aberrant mTOR activation promotes neuroinflammation and disrupts insulin-mediated signalling in neurons and glia. Genetic and pharmacological modulation of mTOR pathways has demonstrated both beneficial and context-dependent outcomes in preclinical models, underscoring the need for precise targeting strategies. The global significance of mTOR in brain ageing and disease underscores its potential both as a biomarker and a therapeutic entry point, with interventions aiming to restore balanced mTOR activity and enhance clearance of toxic aggregates without compromising essential neuronal functions.

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mTOR Signaling in Neurodegenerative Disorders publication trend

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Technical terms

mTOR: A central serine–threonine kinase forming two complexes (mTORC1 and mTORC2) that regulate cell growth, metabolism and proteostasis.

Autophagy: A lysosome-mediated degradation pathway essential for removal of damaged organelles and aggregated proteins.

S6K1 (ribosomal S6 kinase 1): A downstream kinase activated by mTORC1 that modulates protein synthesis and synaptic function.

Amyloid-β (Aβ): A peptide aggregate derived from amyloid precursor protein, associated with synaptic toxicity and network dysfunction in Alzheimer’s disease.

Tau: A microtubule-associated protein that forms neurofibrillary tangles when hyperphosphorylated, contributing to neuronal degeneration.

References

1. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Molecular Neurodegeneration (2021).
2. p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease. Translational Neurodegeneration (2023).
3. Oligomeric β-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway. Aging and Disease (2023).
4. Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives. Frontiers in Pharmacology (2024).
5. Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits. PLOS ONE (2011).