Role of mammalian target of rapamycin in brain physiology and pathology

ZHOU Xiang FU Wei-da CHEN Zhi-chi WANG Tong-tong YE Xing ZHOU Peng CUI Huai-rui SUN Chen-you*

doi:10.16098/j.issn.0529-1356.2018.05.022

PDF(272 KB)

Acta Anatomica Sinica ›› 2018, Vol. 49 ›› Issue (5) : 688-694. DOI: 10.16098/j.issn.0529-1356.2018.05.022

Review

Role of mammalian target of rapamycin in brain physiology and pathology

ZHOU Xiang¹ FU Wei-da² CHEN Zhi-chi ^3,4 WANG Tong-tong ^3,4 YE Xing ^3,4 ZHOU Peng ^3,4 CUI Huai-rui ^3,4 SUN Chen-you ^3,4*

Author information +

History +

Abstract

Target of rapamycin（TOR）and its mammalian ortholog mammalian target of rapamycin(mTOR) have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin. mTOR is a serine/threonine kinase existed in two functionally distinct complexes, mTORC1 and mTORC2, which control many basic cellular functions such as protein synthesis, energy metabolism, cell size, lipid metabolism, autophagy, mitochondria and lysosome biogenesis. In addition, mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development, synaptic plasticity, memory storage, and cognition. Thus it is not surprising that deregulation of mTOR signaling may involve in many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy, cognitive impairment, and brain tumors, while a direct or indirect s timulation of mTORC1 can be beneficial for other pathologies such as depression or axonal growth and regeneration.

Key words

Mammalian target of rapamycin / Nervous system disease / Psychiatric disorders / Rapamycin

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

ZHOU Xiang FU Wei-da CHEN Zhi-chi WANG Tong-tong YE Xing ZHOU Peng CUI Huai-rui SUN Chen-you. Role of mammalian target of rapamycin in brain physiology and pathology[J]. Acta Anatomica Sinica. 2018, 49(5): 688-694 https://doi.org/10.16098/j.issn.0529-1356.2018.05.022

References

［1］ Ehninger D. From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches ［J］. Neuropharmacology, 2013, 68:97-105.

［2］ Laplante M, Sabatini DM. mTOR signaling in growth control and disease ［J］. Cell, 2012, 149（2）:274-293.

［3］ Nixon RA. The role of autophagy in neurodegenerative disease ［J］. Nat Med, 2013，19（8）: 983-997.

［4］ Kim SR, Kareva T, Yarygina O, et al. AAV transduction of dopamine neurons with constitutively active Rheb protects from neurodegeneration and mediates axon regrowth ［J］. Mol Ther, 2012, 20（2）: 275-286.

［5］ Pernet Ⅴ, Schwab ME. Lost in the jungle: new hurdles for optic nerve axon regeneration ［J］. Trends Neurosci, 2014, 37（7）:381-387.

［6］ Zhang J, Ji F, Liu Y, et al. Ezh2 regulates adult hippocampal neurogenesis and memory ［J］. J Neurosci, 2014, 34（15）: 5184-5199.

［7］ Dai J, Bercury KK, Macklin WB. Interaction of mTOR and Erk1/2 signaling to regulate oligodendrocyte differentiation ［J］. Glia, 2014, 62（12）: 2096-2109.

［8］ Li C, Xiao L, Liu X, et al. A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination ［J］. Glia, 2013, 61（5）: 732-749.

［9］ Bercury KK, Dai J, Sachs HH, et al. Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination ［J］. J Neurosci, 2014, 34（13）: 4466-4480.

［10］ Lebrun-Julien F, Bachmann L, Norrmen C, et al. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination ［J］. J Neurosci, 2014, 34（25）: 8432-8448.

［11］ Wahl SE, McLane LE, Bercury KK, et al. Mammalian target of rapamycin promotes oligodendrocyte differentiation, initiation and extent of CNS myelination ［J］. J Neurosci, 2014, 34（13）: 4453-4465.

［12］ Sherman DL, Krols M, Wu LM, et al. Arrest of myelination and reduced axon growth when Schwann cells lack mTOR ［J］. J Neurosci, 2012, 32（5）: 1817-1825.

［13］ Iyer AM, van Scheppingen J, Milenkovic Ⅰ, et al. mTOR hyperactivation in down syndrome hippocampus appears early during development ［J］.J Neuropathol Exp Neurol, 2014, 73（7）: 671-683.

［14］ Ma YQ, Wu DK, Liu JK. mTOR and tau phosphorylated proteins in the hippocampal tissue of rats with type 2 diabetes and Alzheimer’s disease ［J］. Mol Med Rep，2013,7（2）: 623-627.

［15］ Orr ME, Salinas A, Buffenstein R, et al. Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer’s disease pathology ［J］. Neurobiol Aging， 2014, 35（6）: 1233-1242.

［16］ Caccamo A, De Pinto Ⅴ, Messina A, et al. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer’s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature ［J］. J Neurosci， 2014, 34（23）:7988-7998.

［17］ Majumder S, Caccamo A, Medina DX, et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling ［J］. Aging Cell，2012, 11（2）: 326-335.

［18］ Pierce A, Podlutskaya N, Halloran JJ, et al. Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer’s-like deficits in mice modeling the disease ［J］. J Neurochem, 2013, 124(6): 880-893.

［19］ Lin AL, Zheng W, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease ［J］. J Cereb Blood Flow Metab， 2013,33（9）: 1412-1421.

［20］ Cai Z, Yan LJ. Rapamycin, autophagy, and Alzheimer’s disease ［J］. J Biochem Pharmacol Res， 2013, 1（2）: 84-90.

［21］ Tang Z, Bereczki E, Zhang H, et al. Mammalian target of rapamycin (mTOR) mediates tau protein dyshomeostasis: implication for Alzheimer disease ［J］. J Biol Chem, 2013, 288(22): 15556-15570.

［22］ Romani-Aumedes J, Canal M, Martin-Flores N, et al. Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson’s disease ［J］. Cell Death Dis, 2014, 5: e1364.

［23］ Subramaniam S, Napolitano F, Mealer RG, et al. Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia ［J］. Nat Neurosci, 2012, 15(2): 191-193.

［24］ Pryor WM, Biagioli M, Shahani N, et al. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease ［J］. Sci Signal，2014, 7（349）: ra103.

［25］ Mealer RG, Subramaniam S, Snyder SH. Rhes deletion is neuroprotective in the 3-nitropropionic acid model of Huntington’s disease ［J］. J Neurosci, 2013,33(9): 4206-4210.

［26］ Baiamonte BA, Lee FA, Brewer ST, et al. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington’s disease ［J］. PLoS One， 2013, 8（1）: e53606.

［27］ Hyrskyluoto A, Reijonen S, Kivinen J, et al. GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway ［J］. Exp Cell Res，2012, 318（1）: 33-42.

［28］ Mealer RG, Murray AJ, Shahani N, et al. Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy ［J］. J Biol Chem, 2014, 289(6): 3547-3554.

［29］ Lee JH, Tecedor L, Chen YH, et al. Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes ［J］. Neuron， 2015, 85（2）: 303-315.

［30］ Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine ［J］. Neuropharmacology， 2012, 62（1）: 35-41.

［31］ Yu JJ, Zhang Y, Wang Y, et al. Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway ［J］. Psychopharmacology 2013, 225（2）: 361-372.

［32］ Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents ［J］. Trends Neurosci，2012, 35（1）: 47-56.

［33］ Niciu MJ, Henter ID, Luckenbaugh DA, et al. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds［J］. Annu Rev Pharmacol Toxicol, 2014, 54: 119-139.

［34］ Workman ER, Niere F, Raab-Graham KF. mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling ［J］. Neuropharmacology，2013, 73: 192-203.

［35］ Kim CS, Chang PY, Johnston D. Enhancement of dorsal hippocampal activity by knockdown of HCN1 channels leads to anxiolytic-and antidepressant-like behaviors ［J］. Neuron, 2012, 75（3）: 503-516.

［36］ Meffre J, Chaumont-Dubel S, Mannoury la Cour C, et al. 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia ［J］. EMBO Mol Med, 2012, 4（10）: 1043-1056.

［37］ Zhou M, Li W, Huang S, et al. mTOR inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons ［J］. Neuron， 2013, 77（4）: 647-654.

［38］ Ma T, Hoeffer CA, Capetillo-Zarate E, et al. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer’s disease ［J］. PLoS One，2010, 5（9）：e12845.

［39］ Caccamo A, Majumder S, Richardson A, et al. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments ［J］. J Biol Chem, 2010, 285（17）: 13107-13120.

［40］ Boland B, Kumar A, Lee S, et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease ［J］. J Neurosci，2008, 28（27）: 6926-6937.

［41］ Crews L, Spencer B, Desplats P, et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy ［J］. PLoS One， 2010, 5（2）: e9313.

［42］ Tain LS, Mortiboys H, Tao RN, et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss［J］. Nat Neurosci， 2009,12（9）: 1129-1135.

［43］ Xie MQ, Chen ZhCh, Wang TT, et al. The current stayus of neurogenesis in neurotoxin-induced animal models for Parkinson’s diease ［J］. Acta Anatomica Sinica, 2017, 48(5): 497-503. (in Chinese)

谢明琦，陈治池，王彤彤，等. 神经增生在神经性毒物诱导的帕金森动物模型中的研究进展［J］. 解剖学报，2017，48（5）：497-503.

［44］ Howell KR, Kutiyanawalla A, Pillai A. Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex［J］. PLoS One, 2011, 6(5): e20198.