Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration
Download PDF Share Subscribe
logo
All Journals Login

EXO - Beyond the Cell
  1. Home
  2. Articles
  3. Article

Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration

Sung Min Son
1,2,#
,
Weining Li
1,2,#
,
David C. Rubinsztein
1,2,*
*Correspondence to: David C. Rubinsztein, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK. E-mail: dcr1000@cam.ac.uk
EXO. 2026;1:202611. 10.70401/EXO.2026.0009
Received: March 04, 2026Accepted: May 14, 2026Published: May 15, 2026
Tips Icon
This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Neurons rely on precise nutrient-sensing mechanisms to sustain proteostasis and stress resilience across a lifetime. Among these, mechanistic target of rapamycin complex 1 (mTORC1) functions as a central metabolic hub, integrating amino acid availability, growth factor signals, and energetic status to coordinate protein synthesis, autophagy, and neuronal survival. Neuronal mTORC1 regulation is highly specialised, reflecting unique metabolic demands, axonal compartmentalisation, and dependence on long-term homeostatic control that is not shared by non-neuronal cell types. Beyond canonical PI3K–Akt and AMP-activated protein kinase (AMPK) signaling, emerging evidence highlights metabolic intermediates — most notably leucine-derived acetyl-coenzyme A (AcCoA) — as critical upstream regulators that couple nutrient flux to mTORC1 activity via EP300-mediated Raptor acetylation. Chronic dysregulation of these pathways drives persistent mTORC1 hyperactivation, progressive autophagy impairment, and accumulation of proteotoxic species, collectively contributing to neurodegeneration. In Alzheimer’s disease, aberrant mTORC1 activity is linked to tau hyperphosphorylation and amyloid-β accumulation; in Parkinson’s disease, to α-synuclein aggregation and mitophagy failure; in Huntington’s disease, to impaired clearance of mutant huntingtin; and in amyotrophic lateral sclerosis (ALS), to dysregulated proteostasis in motor neurons. This mini review synthesizes current understanding of neuronal mTORC1 regulation, with emphasis on the AcCoA–acetylation axis as an emerging metabolic control mechanism, its disease-specific implications across major neurodegenerative conditions, and the therapeutic opportunities these insights reveal upstream of mTORC1.

Keywords

mTORC1, neurodegeneration, nutrient sensing, autophagy, acetyl-coenzyme A, proteostasis, metabolic flux, neuronal homeostasis

References

  • 1. Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21(10):1133-1145.
    [DOI] [PubMed]
  • 2. Fernandes SA, Demetriades C. The multifaceted role of nutrient sensing and mTORC1 signaling in physiology and aging. Front Aging. 2021;2:707372.
    [DOI] [PubMed] [PMC]
  • 3. Höhn A, Tramutola A, Cascella R. Proteostasis failure in neurodegenerative diseases: Focus on oxidative stress. Oxid Med Cell Longev. 2020;2020:5497046.
    [DOI] [PubMed] [PMC]
  • 4. Querfurth H, Lee HK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegener. 2021;16(1):44.
    [DOI] [PubMed] [PMC]
  • 5. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
    [DOI]
  • 6. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;169(2):361-371.
    [DOI]
  • 7. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012;5(228):ra42.
    [DOI] [PubMed] [PMC]
  • 8. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31(5):1095-1108.
    [DOI] [PubMed] [PMC]
  • 9. Bockaert J, Marin P. mTOR in brain physiology and pathologies. Physiol Rev. 2015;95(4):1157-1187.
    [DOI] [PubMed]
  • 10. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci. 2004;24(44):9760-9769.
    [DOI] [PubMed] [PMC]
  • 11. Akram R, Anwar H, Javed MS, Rasul A, Imran A, Malik SA, et al. Axonal regeneration: Underlying molecular mechanisms and potential therapeutic targets. Biomedicines. 2022;10(12):3186.
    [DOI] [PubMed] [PMC]
  • 12. Bercury KK, Dai J, Sachs HH, Ahrendsen JT, Wood TL, Macklin WB. Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J Neurosci. 2014;34(13):4466-4480.
    [DOI] [PubMed] [PMC]
  • 13. Lebrun-Julien F, Bachmann L, Norrmén C, Trötzmüller M, Köfeler H, Rüegg MA, et al. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. J Neurosci. 2014;34(25):8432-8448.
    [DOI] [PubMed] [PMC]
  • 14. Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M. Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci. 2005;25(49):11300-11312.
    [DOI] [PubMed] [PMC]
  • 15. Hoeffer CA, Klann E. mTOR signaling: At the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33(2):67-75.
    [DOI] [PubMed] [PMC]
  • 16. Huang Z, Mahmood N, Wiebe S, Khoutorsky A, Lacaille JC, Sonenberg N. Cell type-specific mTORC1 signaling and translational control in synaptic plasticity and memory. J Neurochem. 2025;169(11):e70281.
    [DOI] [PubMed] [PMC]
  • 17. Altas B, Romanowski AJ, Bunce GW, Poulopoulos A. Neuronal mTOR outposts: Implications for translation, signaling, and plasticity. Front Cell Neurosci. 2022;16:853634.
    [DOI] [PubMed] [PMC]
  • 18. Son SM, Park SJ, Stamatakou E, Vicinanza M, Menzies FM, Rubinsztein DC. Leucine regulates autophagy via acetylation of the mTORC1 component raptor. Nat Commun. 2020;11:3148.
    [DOI]
  • 19. Girodengo M, Ultanir SK, Bateman JM. Mechanistic target of rapamycin signaling in human nervous system development and disease. Front Mol Neurosci. 2022;15:1005631.
    [DOI] [PubMed] [PMC]
  • 20. Khamsing D, Lebrun S, Fanget I, Larochette N, Tourain C, de Sars V, et al. A role for BDNF- and NMDAR-induced lysosomal recruitment of mTORC1 in the regulation of neuronal mTORC1 activity. Mol Brain. 2021;14(1):112.
    [DOI] [PubMed] [PMC]
  • 21. Urbanska M, Gozdz A, Swiech LJ, Jaworski J. Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons. J Biol Chem. 2012;287(36):30240-30256.
    [DOI] [PubMed] [PMC]
  • 22. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021;101(3):1371-1426.
    [DOI] [PubMed] [PMC]
  • 23. Fernandes SA, Angelidaki DD, Nüchel J, Pan J, Gollwitzer P, Elkis Y, et al. Spatial and functional separation of mTORC1 signalling in response to different amino acid sources. Nat Cell Biol. 2024;26(11):1918-1933.
    [DOI] [PubMed] [PMC]
  • 24. Son SM, Siddiqi FH, Lopez A, Ansari R, Tyrkalska SD, Park SJ, et al. Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition. Neuron. 2025;113(12):1908-1924.e13.
    [DOI] [PubMed]
  • 25. Son SM, Park SJ, Lee H, Siddiqi F, Lee JE, Menzies FM, et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 2019;29(1):192-201.e7.
    [DOI] [PubMed] [PMC]
  • 26. He L, Cho S, Blenis J. mTORC1, the maestro of cell metabolism and growth. Genes Dev. 2025;39(1-2):109-131.
    [DOI] [PubMed] [PMC]
  • 27. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163-175.
    [DOI] [PubMed]
  • 28. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177-189.
    [DOI] [PubMed]
  • 29. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895-904.
    [DOI] [PubMed]
  • 30. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903-915.
    [DOI] [PubMed]
  • 31. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007;9(3):316-323.
    [DOI]
  • 32. Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282(27):20036-20044.
    [DOI] [PubMed]
  • 33. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873-886.
    [DOI] [PubMed] [PMC]
  • 34. Goul C, Peruzzo R, Zoncu R. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease. Nat Rev Mol Cell Biol. 2023;24(12):857-875.
    [DOI] [PubMed] [PMC]
  • 35. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by rag GTPases in nutrient response. Nat Cell Biol. 2008;10(8):935-945.
    [DOI]
  • 36. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320(5882):1496-1501.
    [DOI] [PubMed] [PMC]
  • 37. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature. 2013;497(7448):217-223.
    [DOI]
  • 38. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21(4):183-203.
    [DOI] [PubMed] [PMC]
  • 39. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648-657.
    [DOI] [PubMed]
  • 40. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol Cell. 2002;10(1):151-162.
    [DOI] [PubMed]
  • 41. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577-590.
    [DOI] [PubMed]
  • 42. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214-226.
    [DOI] [PubMed] [PMC]
  • 43. Brugarolas J, Kui L, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004;18(23):2893-2904.
    [DOI] [PubMed] [PMC]
  • 44. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22(2):239-251.
    [DOI] [PubMed] [PMC]
  • 45. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224-236.
    [DOI] [PubMed] [PMC]
  • 46. Eid W, Dauner K, Courtney KC, Gagnon A, Parks RJ, Sorisky A, et al. mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells. Proc Natl Acad Sci U S A. 2017;114(30):7999-8004.
    [DOI] [PubMed] [PMC]
  • 47. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517(7534):302-310.
    [DOI]
  • 48. Efeyan A, Zoncu R, Chang S, Gumper I, Snitkin H, Wolfson RL, et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature. 2013;493(7434):679-683.
    [DOI] [PubMed] [PMC]
  • 49. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A. 1998;95(4):1432-1437.
    [DOI]
  • 50. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981-1991.
    [DOI] [PubMed] [PMC]
  • 51. Ganley IG, Lam DUH, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284(18):12297-12305.
    [DOI] [PubMed] [PMC]
  • 52. Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273(7):3963-3966.
    [DOI] [PubMed]
  • 53. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 2000;150(6):1507-1513.
    [DOI] [PubMed] [PMC]
  • 54. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10(5):307-318.
    [DOI] [PubMed]
  • 55. Napolitano G, Di Malta C, Ballabio A. Non-canonical mTORC1 signaling at the lysosome. Trends Cell Biol. 2022;32(11):920-931.
    [DOI] [PubMed]
  • 56. Valvezan AJ, Manning BD. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab. 2019;1(3):321-333.
    [DOI] [PubMed] [PMC]
  • 57. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002;4(9):658-665.
    [DOI]
  • 58. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17(15):1829-1834.
    [DOI] [PubMed] [PMC]
  • 59. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003;5(6):578-581.
    [DOI]
  • 60. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward rheb. Curr Biol. 2022;32(3):733-734.
    [DOI] [PubMed]
  • 61. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003;13(15):1259-1268.
    [DOI] [PubMed]
  • 62. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005;15(8):702-713.
    [DOI]
  • 63. Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017;552(7685):368-373.
    [DOI]
  • 64. Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem. 2001;276(10):7246-7257.
    [DOI] [PubMed]
  • 65. Nakashima N, Noguchi E, Nishimoto T. Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics. 1999;152(3):853-867.
    [DOI] [PubMed] [PMC]
  • 66. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273(23):14484-14494.
    [DOI] [PubMed]
  • 67. Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature. 2016;536(7615):229-233.
    [DOI]
  • 68. Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell. 2016;165(1):153-164.
    [DOI] [PubMed] [PMC]
  • 69. Gu X, Orozco JM, Saxton RA, Condon KJ, Liu GY, Krawczyk PA, et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science. 2017;358(6364):813-818.
    [DOI] [PubMed] [PMC]
  • 70. Tang X, Zhang Y, Wang G, Zhang C, Wang F, Shi J, et al. Molecular mechanism of S-adenosylmethionine sensing by SAMTOR in mTORC1 signaling. Sci Adv. 2022;8(26):eabn3868.
    [DOI] [PubMed] [PMC]
  • 71. Kim SH, Choi JH, Wang P, Go CD, Hesketh GG, Gingras AC, et al. Mitochondrial threonyl-tRNA synthetase TARS2 is required for threonine-sensitive mTORC1 activation. Mol Cell. 2021;81(2):398-407.e4.
    [DOI] [PubMed]
  • 72. Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, et al. Glutaminolysis activates rag-mTORC1 signaling. Mol Cell. 2012;47(3):349-358.
    [DOI] [PubMed]
  • 73. Meng D, Yang Q, Wang H, Melick CH, Navlani R, Frank AR, et al. Glutamine and asparagine activate mTORC1 independently of Rag GTPases. J Biol Chem. 2020;295(10):2890-2899.
    [DOI] [PubMed] [PMC]
  • 74. Kobayashi T, Shimabukuro-Demoto S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity. 2014;41(3):375-388.
    [DOI] [PubMed]
  • 75. Zhou Y, Zhou Z, Peng J, Loor JJ. Methionine and valine activate the mammalian target of rapamycin complex 1 pathway through heterodimeric amino acid taste receptor (TAS1R1/TAS1R3) and intracellular Ca2+ in bovine mammary epithelial cells. J Dairy Sci. 2018;101(12):11354-11363.
    [DOI] [PubMed]
  • 76. Wolfson RL, Sabatini DM. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 2017;26(2):301-309.
    [DOI] [PubMed] [PMC]
  • 77. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340(6136):1100-1106.
    [DOI] [PubMed] [PMC]
  • 78. Ivanova I, Shen K. Structures and functions of the human GATOR1 complex. Subcell Biochem. 2024;104:269-294.
    [DOI] [PubMed] [PMC]
  • 79. Loissell-Baltazar YA, Dokudovskaya S. SEA and GATOR 10 years later. Cells. 2021;10(10):2689.
    [DOI]
  • 80. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351(6268):43-48.
    [DOI] [PubMed] [PMC]
  • 81. Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016;351(6268):53-58.
    [DOI] [PubMed] [PMC]
  • 82. Chen J, Ou Y, Luo R, Wang J, Wang D, Guan J, et al. SAR1B senses leucine levels to regulate mTORC1 signalling. Nature. 2021;596(7871):281-284.
    [DOI] [PubMed] [PMC]
  • 83. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290-303.
    [DOI]
  • 84. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012;150(6):1196-1208.
    [DOI]
  • 85. Colaço A, Jäättelä M. Ragulator-a multifaceted regulator of lysosomal signaling and trafficking. J Cell Biol. 2017;216(12):3895-3898.
    [DOI] [PubMed] [PMC]
  • 86. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678-683.
    [DOI] [PubMed] [PMC]
  • 87. Jung J, Genau HM, Behrends C. Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol Cell Biol. 2015;35(14):2479-2494.
    [DOI] [PubMed] [PMC]
  • 88. Rebsamen M, Pochini L, Stasyk T, de Araújo ME, Galluccio M, Kandasamy RK, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015;519(7544):477-481.
    [DOI] [PubMed] [PMC]
  • 89. Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, et al. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015;347(6218):188-194.
    [DOI]
  • 90. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495-505.
    [DOI] [PubMed] [PMC]
  • 91. Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol. 2013;202(7):1107-1122.
    [DOI] [PubMed] [PMC]
  • 92. Goberdhan DCI, Wilson C, Harris AL. Amino acid sensing by mTORC1: Intracellular transporters mark the spot. Cell Metab. 2016;23(4):580-589.
    [DOI]
  • 93. Beugnet A, Tee AR, Taylor PM, Proud CG. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J. 2003;372(Pt 2):555-566.
    [DOI] [PubMed] [PMC]
  • 94. Christie GR, Hajduch E, Hundal HS, Proud CG, Taylor PM. Intracellular sensing of amino acids in xenopus laevis oocytes stimulates p70 S6 kinase in a target of rapamycin-dependent manner. J Biol Chem. 2002;277(12):9952-9957.
    [DOI]
  • 95. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell. 2012;149(2):410-424.
    [DOI]
  • 96. Bonfils G, Jaquenoud M, Bontron S, Ostrowicz C, Ungermann C, De Virgilio C. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol Cell. 2012;46(1):105-110.
    [DOI] [PubMed]
  • 97. Kim JH, Lee C, Lee M, Wang H, Kim K, Park SJ, et al. Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. Nat Commun. 2017;8(1):732.
    [DOI] [PubMed] [PMC]
  • 98. Kim S, Yoon I, Son J, Park J, Kim K, Lee JH, et al. Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation. Cell Rep. 2021;35(4):109031.
    [DOI] [PubMed]
  • 99. Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer. 2023;23(3):156-172.
    [DOI]
  • 100. Mariño G, Pietrocola F, Eisenberg T, Kong Y, Ahmad Malik S, Andryushkova A, et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell. 2014;53(5):710-725.
    [DOI]
  • 101. Zhou WH, Luo Y, Li RX, Degrace P, Jourdan T, Qiao F, et al. Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of Raptor in zebrafish. J Biol Chem. 2023;299(10):105220.
    [DOI] [PubMed] [PMC]
  • 102. He A, Chen X, Tan M, Chen Y, Lu D, Zhang X, et al. Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation. Mol Cell. 2020;79(1):30-42.e4.
    [DOI] [PubMed] [PMC]
  • 103. Son SM, Park SJ, Breusegem SY, Larrieu D, Rubinsztein DC. p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome. Nat Cell Biol. 2024;26(2):235-249.
    [DOI] [PubMed] [PMC]
  • 104. Tseng CS, Chao YW, Liu YH, Huang YS, Chao HW. Dysregulated proteostasis network in neuronal diseases. Front Cell Dev Biol. 2023;11:1075215.
    [DOI]
  • 105. Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28.
    [DOI] [PubMed] [PMC]
  • 106. Martinez-Vicente M. Neuronal mitophagy in neurodegenerative diseases. Front Mol Neurosci. 2017;10:64.
    [DOI]
  • 107. Li YY, Qin ZH, Sheng R. The multiple roles of autophagy in neural function and diseases. Neurosci Bull. 2024;40(3):363-382.
    [DOI] [PubMed] [PMC]
  • 108. Metaxakis A, Pavlidis M, Tavernarakis N. Neuronal atg1 coordinates autophagy induction and physiological adaptations to balance mTORC1 signalling. Cells. 2023;12(16):2024.
    [DOI] [PubMed] [PMC]
  • 109. Palmer JE, Wilson N, Son SM, Obrocki P, Wrobel L, Rob M, et al. Autophagy, aging, and age-related neurodegeneration. Neuron. 2025;113(1):29-48.
    [DOI] [PubMed]
  • 110. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54(4):412-436.
    [DOI]
  • 111. Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol. 2023;19(1):19-38.
    [DOI]
  • 112. Festa BP, Barbosa AD, Rob M, Rubinsztein DC. The pleiotropic roles of autophagy in Alzheimer’s disease: From pathophysiology to therapy. Curr Opin Pharmacol. 2021;60:149-157.
    [DOI] [PubMed] [PMC]
  • 113. Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magrí A, et al. Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem. 2011;286(11):8924-8932.
    [DOI] [PubMed] [PMC]
  • 114. Tramutola A, Triplett JC, di Domenico F, Niedowicz DM, Murphy MP, Coccia R, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): Analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem. 2015;133(5):739-749.
    [DOI] [PubMed]
  • 115. García Porta C, Mahfooz K, Komorowska J, Garcia-Rates S, Greenfield S. A novel 14mer peptide inhibits autophagic flux via selective activation of the mTORC1 signalling pathway: Implications for Alzheimer’s disease. Int J Mol Sci. 2024;25(23):12837.
    [DOI] [PubMed] [PMC]
  • 116. Zhang W, Xu C, Sun J, Shen HM, Wang J, Yang C. Impairment of the autophagy-lysosomal pathway in Alzheimer’s diseases: Pathogenic mechanisms and therapeutic potential. Acta Pharm Sin B. 2022;12(3):1019-1040.
    [DOI] [PubMed] [PMC]
  • 117. Zhang Y, Lv Y, Yang T, Liu Q, Guo Q. Insulin resistance and Alzheimer’s disease: Exploring research hotspots and frontiers from a bibliometric and visual analysis (2005-2024). J Alzheimers Dis Rep. 2025;9:25424823251361056.
    [DOI] [PubMed] [PMC]
  • 118. Barone E, di Domenico F, Perluigi M, Butterfield DA. The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease. Free Radic Biol Med. 2021;176:16-33.
    [DOI] [PubMed] [PMC]
  • 119. Atabi F, Moassesfar M, Nakhaie T, Bagherian M, Hosseinpour N, Hashemi M. A systematic review on type 3 diabetes: Bridging the gap between metabolic dysfunction and Alzheimer’s disease. Diabetol Metab Syndr. 2025;17(1):356.
    [DOI] [PubMed] [PMC]
  • 120. Kommaddi RP, Gowaikar R, P a H, Diwakar L, Singh K, Mondal A. Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer’s disease mouse model. J Biol Chem. 2024;300(2):105619.
    [DOI] [PubMed] [PMC]
  • 121. Davoody S, Asgari Taei A, Khodabakhsh P, Dargahi L. mTOR signaling and Alzheimer’s disease: What we know and where we are? CNS Neurosci Ther. 2024;30(4):e14463.
    [DOI] [PubMed] [PMC]
  • 122. Morawe MP, Liao F, Amberg W, van Bergeijk J, Chang R, Gulino M, et al. Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain. Eur J Pharmacol. 2022;934:175301.
    [DOI] [PubMed]
  • 123. Wu Y, Li T, Jiang X, Ling J, Zhao Z, Zhu J, et al. (-)-epicatechin rescues memory deficits by activation of autophagy in a mouse model of tauopathies. MedComm. 2025;6(4):e70144.
    [DOI] [PubMed] [PMC]
  • 124. Xie PL, Zheng MY, Han R, Chen WX, Mao JH. Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: Current review and perspectives. Front Pharmacol. 2024;15:1366061.
    [DOI] [PubMed] [PMC]
  • 125. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(10291):2284-2303.
    [DOI]
  • 126. Henrich MT, Oertel WH, Surmeier DJ, Geibl FF. Mitochondrial dysfunction in Parkinson’s disease - a key disease hallmark with therapeutic potential. Mol Neurodegener. 2023;18(1):83.
    [DOI] [PubMed] [PMC]
  • 127. Kim JY, Kwon YG, Kim YM. The stress-responsive protein REDD1 and its pathophysiological functions. Exp Mol Med. 2023;55(9):1933-1944.
    [DOI] [PubMed] [PMC]
  • 128. Khan MR, Yin X, Kang SU, Mitra J, Wang H, Ryu T, et al. Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease. Sci Transl Med. 2023;15(724):eadd0499.
    [DOI] [PubMed]
  • 129. Jiang A, Handley RR, Lehnert K, Snell RG. From pathogenesis to therapeutics: A review of 150 years of Huntington’s disease research. Int J Mol Sci. 2023;24(16):13021.
    [DOI]
  • 130. Chang CP, Wu CW, Chern Y. Metabolic dysregulation in Huntington’s disease: Neuronal and glial perspectives. Neurobiol Dis. 2024;201:106672.
    [DOI] [PubMed]
  • 131. Paul S, Dansithong W, Figueroa KP, Gandelman M, Scoles DR, Pulst SM. Staufen1 in human neurodegeneration. Ann Neurol. 2021;89(6):1114-1128.
    [DOI]
  • 132. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585-595.
    [DOI] [PubMed]
  • 133. Stavrides P, Goulbourne CN, Peddy J, Huo C, Rao M, Khetarpal V, et al. mTOR inhibition in Q175 Huntington’s disease model mice facilitates neuronal autophagy and mutant huntingtin clearance. Elife. 2025;14:RP104979.
    [DOI] [PubMed] [PMC]
  • 134. Pryor WM, Biagioli M, Shahani N, Swarnkar S, Huang WC, Page DT, et al. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Sci Signal. 2014;7(349):ra103.
    [DOI] [PubMed]
  • 135. St-Cyr S, Child DD, Giaime E, Smith AR, Pascua CJ, Hahm S, et al. Huntington’s disease phenotypes are improved via mTORC1 modulation by small molecule therapy. PLoS One. 2022;17(8):e0273710.
    [DOI] [PubMed] [PMC]
  • 136. Pérez-Sisqués L, Solana-Balaguer J, Campoy-Campos G, Martín-Flores N, Sancho-Balsells A, Vives-Isern M, et al. RTP801/REDD1 is involved in neuroinflammation and modulates cognitive dysfunction in Huntington’s disease. Biomolecules. 2021;12(1):34.
    [DOI] [PubMed] [PMC]
  • 137. Corbet GA, Wheeler JR, Parker R, Weskamp K. TDP43 ribonucleoprotein granules: Physiologic function to pathologic aggregates. RNA Biol. 2021;18(sup1):128-138.
    [DOI] [PubMed] [PMC]
  • 138. Verde EM, Secco V, Ghezzi A, Mandrioli J, Carra S. Molecular mechanisms of protein aggregation in ALS-FTD: Focus on TDP-43 and cellular protective responses. Cells. 2025;14(10):680.
    [DOI] [PubMed] [PMC]
  • 139. de Boer EMJ, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, et al. TDP-43 proteinopathies: A new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2021;92(1):86-95.
    [DOI]
  • 140. Nogueira-Machado JA, Rocha-Silva F, Gomes NA. The role of mTOR in amyotrophic lateral sclerosis. Biomedicines. 2025;13(4):952.
    [DOI]
  • 141. Amick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Mol Biol Cell. 2016;27(20):3040-3051.
    [DOI] [PubMed] [PMC]
  • 142. Beckers J, Tharkeshwar AK, van Damme P. C9orf72 ALS-FTD: Recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels. Autophagy. 2021;17(11):3306-3322.
    [DOI] [PubMed] [PMC]
  • 143. Diab R, Pilotto F, Saxena S. Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology. Front Cell Neurosci. 2023;17:1086895.
    [DOI] [PubMed] [PMC]
  • 144. Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X, et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy. 2011;7(4):412-425.
    [DOI] [PubMed]
  • 145. Granatiero V, Sayles NM, Savino AM, Konrad C, Kharas MG, Kawamata H, et al. Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1G93A astrocytes. Autophagy. 2021;17(12):4029-4042.
    [DOI] [PubMed] [PMC]
  • 146. Rudnick ND, Griffey CJ, Guarnieri P, Gerbino V, Wang X, Piersaint JA, et al. Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS. Proc Natl Acad Sci U S A. 2017;114(39):E8294-E8303.
    [DOI] [PubMed] [PMC]
  • 147. Caccamo A, Magrì A, Medina DX, Wisely EV, López-Aranda MF, Silva AJ, et al. mTOR regulates tau phosphorylation and degradation: Implications for Alzheimer’s disease and other tauopathies. Aging Cell. 2013;12(3):370-380.
    [DOI] [PubMed] [PMC]
  • 148. Zhang X, Chen S, Song L, Tang Y, Shen Y, Jia L, et al. MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy. 2014;10(4):588-602.
    [DOI] [PubMed] [PMC]
  • 149. Gasser J, Gillet G, Valadas JS, Rouvière L, Kotian A, Fan W, et al. Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia. Front Mol Neurosci. 2023;16:1191324.
    [DOI] [PubMed] [PMC]
  • 150. Wilton DK, Mastro K, Heller MD, Gergits FW, Willing CR, Fahey JB, et al. Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease. Nat Med. 2023;29(11):2866-2884.
    [DOI] [PubMed] [PMC]
  • 151. Festa BP, Siddiqi FH, Jimenez-Sanchez M, Won H, Rob M, Djajadikerta A, et al. Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration. Neuron. 2023;111(13):2021-2037.e12.
    [DOI] [PubMed]
  • 152. Festa BP, Siddiqi FH, Jimenez-Sanchez M, Rubinsztein DC. Microglial cytokines poison neuronal autophagy via CCR5, a druggable target. Autophagy. 2024;20(4):949-951.
    [DOI]
  • 153. Cano A, Fonseca E, Ettcheto M, Sánchez-López E, de Rojas I, Alonso-Lana S, et al. Epilepsy in neurodegenerative diseases: Related drugs and molecular pathways. Pharmaceuticals (Basel). 2021;14(10):1057.
    [DOI] [PubMed] [PMC]
  • 154. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84(2):275-291.
    [DOI]

© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Publisher’s Note

Science Exploration remains a neutral stance on jurisdictional claims in published maps and institutional affiliations. The views expressed in this article are solely those of the author(s) and do not reflect the opinions of the Editors or the publisher.

Share And Cite

×

Science Exploration Style
Son SM, Li W, Rubinsztein DC. Nutrient-sensing and mTORC1 regulation in neuronal homeostasis: from metabolic signaling to neurodegeneration. EXO. 2026;1:202611. https://doi.org/10.70401/EXO.2026.0009

Submit a Manuscript
Author Instructions
Cite this Article
Export Citation
Article Metrics
0
View
0
Download
Cited
Article Updates
Related Articles
Citation Icon Get citation

EXO - Beyond the Cell

exojournal@sciexplor.com

Navigation

About the Journal
Editorial Process
Author Instructions
Editorial Board
Editorial Policies
Contact Us

Follow us