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Balancing Mtor Signaling and Autophagy in the Treatment of Parkinson's Disease

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Balancing Mtor Signaling and Autophagy in the Treatment of Parkinson's Disease Review Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease Zhou Zhu 1 , Chuanbin Yang 1, Ashok Iyaswamy 1, Senthilkumar Krishnamoorthi 1, Sravan Gopalkrishnashetty Sreenivasmurthy 1, Jia Liu 1, Ziying Wang 1, Benjamin Chun-Kit Tong 1 , Juxian Song 2, Jiahong Lu 3, King-Ho Cheung 1 and Min Li 1,* 1 Mr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China; [email protected] (Z.Z.); [email protected] (C.Y.); [email protected] (A.I.); [email protected] (S.K.); [email protected] (S.G.S.); [email protected] (J.L.); [email protected] (Z.W.); [email protected] (B.C.-K.T.); [email protected] (K.-H.C.) 2 Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; [email protected] 3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR 999078, China; [email protected] * Correspondence: [email protected]; Tel: +852-3411-2919 Received: 15 January 2019; Accepted: 1 February 2019; Published: 8 February 2019 Abstract: The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development. Keywords: mTOR; autophagy; Parkinson’s disease 1. Introduction of mTOR The target of rapamycin (TOR) was first identified as a target protein of rapamycin, encoded by TOR1 and TOR2 alleles, through screening of rapamycin-resistant mutant yeast [1]. This study showed rapamycin could form a complex with FK506-binding protein (FKBP), leading to cell cycle arrest in the G1 phase, which is mediated by TOR1 and TOR2 [1]. Subsequent studies of mammalian cells found homologous proteins, termed mammalian targets of rapamycin (mTOR), which shared more than 40% consistency in amino acid sequence with yeast TOR1 and TOR2 [2]. In addition, the function of mTOR was also related to the rapamycin-FKBP12 induced cell cycle arrest [2,3]. mTOR, which is also termed as FKBP12-rapamycin complex-associated protein (FRAP), is a conserved serine/threonine protein kinase, and mTOR belongs to the phosphoinositide-3-kinase (PI3K)-related kinase family of protein kinases [4]. mTOR constitutes the catalytic component of two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (Figure1)[5]. Int. J. Mol. Sci. 2019, 20, 728; doi:10.3390/ijms20030728 www.mdpi.com/journal/ijms Int. J. Mol. Sci. Sci. 20192019,, 1920,, x 728 2 2of of 15 mTORC1 contains mTOR, mammalian lethal with SEC13 protein 8 (mLST8), DEP (DVL, Egl-10, pleckstrin)-domainmTORC1 contains containing mTOR, mTOR mammalian-interacting lethal protein with SEC13 (DEPTOR), protein pr 8oline-rich (mLST8), Akt DEP substrate (DVL, Egl-10, of 40 pleckstrin)-domainkD (PRAS40), and regulatory containing associated mTOR-interacting protein of proteinmammalian (DEPTOR), target of proline-rich rapamycin Akt(Raptor) substrate (Figure of 401) [6–10]. kD (PRAS40), In this complex, and regulatory mTOR-combined associated DEPTOR protein and of mammalian PRAS40 can targetnegatively of rapamycin regulate mTORC1 (Raptor) (Figureactivity1 [6,10].)[ 6– mTORC110]. In plays this complex,a key role in mTOR-combined regulating cell growth, DEPTOR cell size, and and PRAS40 proliferation can negatively [8,11,12]. regulatemTORC1 mTORC1 is a core activitycomponent [6,10 in]. a mTORC1 series of playssignaling a key networks. role in regulatingAdditionally, cell it growth, senses different cell size, andstimuli proliferation such as insulin [8,11 level,,12]. energy mTORC1 level, is and a coreamino component acid level, and in a is seriesinvolved of signalingin protein synthesis, networks. Additionally,lipid metabolism, it senses glycolytic different metabolism, stimuli suchand autophagy as insulin [13,14]. level, energy level, and amino acid level, and ismTORC2 involved consists in protein of synthesis,mTOR, mLST8, lipid metabolism, DEPTOR, glycolyticrapamycin-insensitive metabolism, andcompanion autophagy of [mTOR13,14]. (Rictor),mTORC2 mammalian consists stress-activated of mTOR, mLST8, map kinase-int DEPTOR,eracting rapamycin-insensitive protein 1 (mSIN1), companion and protein ofobserved mTOR (Rictor),with Rictor mammalian (Protor) (Figure stress-activated 1) [6,15–19]. map mTORC2 kinase-interacting also regulates protein many 1 (mSIN1), cellular processes, and protein such observed as cell withgrowth, Rictor proliferation, (Protor) (Figure metabolism,1)[ 6,15 and–19]. cell mTORC2 motility also viaregulates the AGC many kinase cellular family processes, member suchAkt, asserum/glucocorticoid cell growth, proliferation, regulated metabolism, kinase (SGK), and prot cellein motility kinase viaC (PKC), the AGC and kinasefilamin familyA [20–23]. member The Akt,well-known serum/glucocorticoid substrate of mTORC2 regulated is Akt. kinase Akt (SGK), can be proteinfully activated kinase Cwhen (PKC), it is and phosphorylated filamin A [20 by–23 3-]. Thephosphoinositide well-known substrate dependent of mTORC2 protein iskinase-1 Akt. Akt can(PDK1) be fully at activatedThr308 whensite, itand is phosphorylated subsequently byphosphorylated 3-phosphoinositide by mTORC2 dependent at Ser473 protein site kinase-1[24,25]. Actually, (PDK1) atYang Thr308 et al. site, found and that subsequently mSIN1, a phosphorylatedcomponent of mTORC2, by mTORC2 mediates at Ser473 a sitepositive [24,25 f].eedback Actually, loop Yang between et al. found mTORC2 that mSIN1, and Akt a component [26]. The ofphosphorylation mTORC2, mediates of mSIN1 a positive at Thr86 feedback site, loop which between is induced mTORC2 by andphospho- Akt [26Akt,]. The enhances phosphorylation mTORC2 ofactivity mSIN1 in atresponse Thr86 site, to growth which isfactors induced [26,27]. by phospho-Akt, enhances mTORC2 activity in response to growthThe factors PI3K/Akt/mTOR [26,27]. signaling pathway has been extensively studied because it plays a crucial role inThe controlling PI3K/Akt/mTOR cell growth, signaling in maintaining pathway has cell been viability, extensively and in studied determining because a it cell’s plays life a crucial span role[28,29]. in controlling Insulin receptor cell growth, substrate in maintaining (IRS) activates cell phosphatidylinositol viability, and in determining 3-kinase a (PI3K) cell’s life upon span presence [28,29]. Insulinof growth receptor factors, substrate recruiting (IRS) PIP2 activatesto the plasma phosphatidylinositol membrane, and enhancing 3-kinase (PI3K)transformation upon presence of PIP2 ofto growthPIP3. PIP3 factors, promotes recruiting the PIP2 phosphorylation to the plasma membrane,of Akt on andthe enhancingThr308 and transformation Ser473 sites ofby PIP2 PDK1 to PIP3.and PIP3mTORC2, promotes respectively. the phosphorylation Once being offully Akt onactivated, the Thr308 Akt and phosphorylates Ser473 sites byand PDK1 inhibits and mTORC2,tuberous respectively.sclerosis complex Once (TSC), being which fully activated, is the negative Akt phosphorylates regulator of Ras and homolog inhibits enriched tuberous in sclerosis brain (Rheb) complex and (TSC),finally whichleads to is the negativeactivation regulator of mTORC1 of Ras [30]. homolog There enrichedare two well-established in brain (Rheb) anddownstream finally leads effectors to the activationbeing phosphorylated of mTORC1 [by30 ].mTORC1, There are p70 two ribosomal well-established S6 kinase downstream (P70S6K) and effectors eukaryotic being phosphorylatedinitiation factor by4E mTORC1,(eIF4E) binding p70 ribosomal protein 1 S6(4EBP1); kinase (P70S6K)both of th andem are eukaryotic main regulators initiation of factor cap-dependent 4E (eIF4E) bindingprotein proteinsynthesis 1 (4EBP1);[31,32]. both of them are main regulators of cap-dependent protein synthesis [31,32]. Figure 1. Protein components of mTORC1 and mTORC2. Both mTORC1 and mTORC2 include the same Figure 1. Protein components of mTORC1 and mTORC2. Both mTORC1 and mTORC2 include the macromolecules such as mTOR, mLST8, and DEPTOR. Apart from these components, mTORC1 also same macromolecules such as mTOR, mLST8, and DEPTOR. Apart from these components, mTORC1 contains PRAS40 and Raptor. Correspondingly, mTORC2 contains mSIN1, Rictor, and Protor. also contains PRAS40 and Raptor. Correspondingly, mTORC2 contains mSIN1, Rictor, and Protor. Abbreviation: mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; mTOR, Mammalian targets Abbreviation: mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; mTOR, Mammalian
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