Fighting neurodegeneration with rapamycin: mechanistic insights (original) (raw)

• Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).
  Article CAS Google Scholar
• Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122–1128 (2004).
  Article CAS PubMed Google Scholar
• Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).
  Article CAS PubMed Google Scholar
• Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
  Article CAS PubMed Google Scholar
• Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).
  Article CAS PubMed Google Scholar
• Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10, 151–162 (2002).
  Article CAS PubMed Google Scholar
• Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002).
  Article CAS PubMed Google Scholar
• Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).
  Article CAS PubMed Google Scholar
• Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & 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. 13, 1259–1268 (2003).
  Article CAS PubMed Google Scholar
• Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nature Cell Biol. 13, 453–460 (2011).
  Article CAS PubMed Google Scholar
• Haghighat, A., Mader, S., Pause, A. & Sonenberg, N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 14, 5701–5709 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).
  Article CAS PubMed Google Scholar
• Yamasaki, S. & Anderson, P. Reprogramming mRNA translation during stress. Curr. Opin. Cell Biol. 20, 222–226 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neurosci. 12, 1129–1135 (2009). In this article, rapamycin was shown to suppress flight muscle degeneration, climbing deficits, mitochondrial alterations and dopaminergic neurodegeneration in D. melanogaster Pink1 or park knockout models of Parkinson's disease by activating 4E-BP.
  Article CAS PubMed Google Scholar
• Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson, K. F., Wu, W. J. & Cerione, R. A. Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex. J. Biol. Chem. 275, 37307–37310 (2000).
  Article CAS PubMed Google Scholar
• Wang, X. et al. Regulation of elongation factor 2 kinase by p90_RSK1_ and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477–480 (2005).
  Article CAS PubMed Google Scholar
• Ma, X. M., Yoon, S. O., Richardson, C. J., Julich, K. & Blenis, J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133, 303–313 (2008).
  Article CAS PubMed Google Scholar
• Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
  Article CAS PubMed Google Scholar
• Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
  Article CAS PubMed Google Scholar
• Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).
  Article CAS PubMed Google Scholar
• Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004). This study provided the first demonstration that rapamycin is able to attenuate pathology in experimental in vivo models of neurodegeneration by inducing autophagy-mediated degradation of aggregate-prone proteins.
  Article CAS PubMed Google Scholar
• Charest, P. G. et al. A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Dev. Cell 18, 737–749 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, S. et al. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 16, 4572–4583 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, J., Dibble, C. C., Matsuzaki, M. & Manning, B. D. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol. 28, 4104–4115 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).
  Article CAS PubMed Google Scholar
• Facchinetti, V. et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J. 27, 1932–1943 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
  Article CAS PubMed Google Scholar
• Guertin, D. A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).
  Article CAS PubMed Google Scholar
• Garcia-Martinez, J. M. & Alessi, D. R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416, 375–385 (2008).
  Article CAS PubMed Google Scholar
• Ikenoue, T., Inoki, K., Yang, Q., Zhou, X. & Guan, K. L. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J. 27, 1919–1931 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wong, E. & Cuervo, A. M. Autophagy gone awry in neurodegenerative diseases. Nature Neurosci. 13, 805–811 (2010).
  Article CAS PubMed Google Scholar
• Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).
  Article CAS PubMed Google Scholar
• Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166–1175 (2010). This study demonstrates that rapamycin protects against dopaminergic neuron cell death in the MPTP mouse model of Parkinson's disease by blockade of mTORC1-dependent translation of the pro-cell death protein RTP801.
  Article CAS PubMed PubMed Central Google Scholar
• Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535–12544 (2010). This study demonstrates that rapamycin protects against MPTP-induced dopaminergic neurodegeneration by boosting lysosomal biogenesis, restoring the number of lysosomes, enhancing autophagosome–lysosome fusion and increasing lysosome-mediated clearance of accumulated autophagosomes.
  Article CAS PubMed PubMed Central Google Scholar
• Przedborski, S. & Vila, M. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. Ann. N. Y. Acad. Sci. 991, 189–198 (2003).
  Article CAS PubMed Google Scholar
• Malagelada, C., Ryu, E. J., Biswas, S. C., Jackson-Lewis, V. & Greene, L. A. RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. J. Neurosci. 26, 9996–10005 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Malagelada, C., Jin, Z. H. & Greene, L. A. RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J. Neurosci. 28, 14363–14371 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ries, V. et al. Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease. Proc. Natl Acad. Sci. USA 103, 18757–18762 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Vila, M., Bove, J., Dehay, B., Rodriguez-Muela, N. & Boya, P. Lysosomal membrane permeabilization in Parkinson disease. Autophagy 7, 98–100 (2011).
  Article PubMed Google Scholar
• Chu, Y., Dodiya, H., Aebischer, P., Olanow, C. W. & Kordower, J. H. Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to α-synuclein inclusions. Neurobiol. Dis. 35, 385–398 (2009).
  Article CAS PubMed Google Scholar
• Anglade, P. et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol. Histopathol. 12, 25–31 (1997).
  CAS PubMed Google Scholar
• Sarkar, S., Ravikumar, B., Floto, R. A. & Rubinsztein, D. C. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16, 46–56 (2009).
  Article CAS PubMed Google Scholar
• Demarchi, F. et al. Calpain is required for macroautophagy in mammalian cells. J. Cell Biol. 175, 595–605 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Cullen, V. et al. Acid β-glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α-synuclein processing. Ann. Neurol. 69, 940–953 (2011).
  Article CAS PubMed Google Scholar
• Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).
  Article CAS PubMed Google Scholar
• Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Pan, T. et al. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25 (2008).
  Article CAS PubMed Google Scholar
• Crews, L. et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy. PLoS ONE 5, e9313 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578–13588 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, W. H. et al. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric α-synuclein. Am. J. Pathol. 175, 736–747 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chem. Biol. 4, 295–305 (2008).
  Article CAS Google Scholar
• Sarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A. & Rubinsztein, D. C. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J. Biol. Chem. 282, 5641–5652 (2007).
  Article CAS PubMed Google Scholar
• Sarkar, S. et al. Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nature Chem. Biol. 3, 331–338 (2007).
  Article CAS Google Scholar
• Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).
  Article CAS PubMed Google Scholar
• Pan, T. et al. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 164, 541–551 (2009).
  Article CAS PubMed Google Scholar
• Tait, S. W. & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature Rev. Mol. Cell Biol. 11, 621–632 (2010).
  Article CAS Google Scholar
• Vila, M. & Przedborski, S. Genetic clues to the pathogenesis of Parkinson's disease. Nature Med. 10, S58–S62 (2004).
  Article CAS PubMed Google Scholar
• Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12, 119–131 (2010).
  Article CAS PubMed Google Scholar
• Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS. Biol. 8, e1000298 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
  Article CAS PubMed Google Scholar
• Vila, M. et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 2837–2842 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Vila, M. & Przedborski, S. Targeting programmed cell death in neurodegenerative diseases. Nature Rev. Neurosci. 4, 365–375 (2003).
  Article CAS Google Scholar
• Perier, C. et al. Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc. Natl Acad. Sci. USA 102, 19126–19131 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Perier, C. et al. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease. Proc. Natl Acad. Sci. USA 104, 8161–8166 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ravikumar, B., Berger, Z., Vacher, C., O'Kane, C. J. & Rubinsztein, D. C. Rapamycin pre-treatment protects against apoptosis. Hum. Mol. Genet. 15, 1209–1216 (2006).
  Article CAS PubMed Google Scholar
• Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Santini, E., Heiman, M., Greengard, P., Valjent, E. & Fisone, G. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2, ra36 (2009).
  Article PubMed Google Scholar
• Ross, C. A. & Tabrizi, S. J. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83–98 (2011).
  Article CAS PubMed Google Scholar
• Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).
  Article CAS PubMed Google Scholar
• Sarkar, S. et al. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).
  Article CAS PubMed Google Scholar
• Tsvetkov, A. S. et al. A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc. Natl Acad. Sci. USA 107, 16982–16987 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nature Neurosci. 13, 567–576 (2010).
  Article CAS PubMed Google Scholar
• Wang, T., Lao, U. & Edgar, B. A. TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J. Cell Biol. 186, 703–711 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Rose, C. et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease. Hum. Mol. Genet. 19, 2144–2153 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Fox, J. H. et al. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease. Mol. Neurodegener. 5, 26 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• King, M. A. et al. Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis. Mol. Pharmacol. 73, 1052–1063 (2008).
  Article CAS PubMed Google Scholar
• Ittner, L. M. & Gotz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease. Nature Rev. Neurosci. 12, 65–72 (2011).
  Article CAS Google Scholar
• Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Caccamo, A. et al. Naturally secreted amyloid-β increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J. Biol. Chem. 286, 8924–8932 (2011). References 85 and 86 demonstrate an Aβ-induced hyperactivation of mTOR in a triple-transgenic mouse model of Alzheimer's disease. In these animals, rapamycin treatment decreased intraneuronal Aβ accumulations, attenuated tau pathology and rescued cognitive deficits.
  Article CAS PubMed PubMed Central Google Scholar
• Meske, V., Albert, F. & Ohm, T. G. Coupling of mammalian target of rapamycin with phosphoinositide 3-kinase signaling pathway regulates protein phosphatase 2A- and glycogen synthase kinase-3-dependent phosphorylation of Tau. J. Biol. Chem. 283, 100–109 (2008).
  Article CAS PubMed Google Scholar
• Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Garelick, M. G. & Kennedy, B. K. TOR on the brain. Exp. Gerontol. 46, 155–163 (2011).
  Article CAS PubMed Google Scholar
• Casadio, A. et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237 (1999).
  Article CAS PubMed Google Scholar
• Tischmeyer, W. et al. Rapamycin-sensitive signalling in long-term consolidation of auditory cortex-dependent memory. Eur. J. Neurosci. 18, 942–950 (2003).
  Article PubMed Google Scholar
• Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Med. 14, 843–848 (2008).
  Article CAS PubMed Google Scholar
• Puighermanal, E. et al. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nature Neurosci. 12, 1152–1158 (2009).
  Article CAS PubMed Google Scholar
• Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006).
  Article CAS PubMed Google Scholar
• Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).
  Article CAS PubMed Google Scholar
• Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).
  CAS PubMed PubMed Central Google Scholar
• Hung., S. Y., Huang, W. P., Liou, H. C. & Fu, W. M. Autophagy protects neuron from Aβ-induced cytotoxicity. Autophagy 5, 502–510 (2009).
  Article CAS PubMed Google Scholar
• Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258–277 (2011).
  Article PubMed Google Scholar
• Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005).
  Article PubMed Google Scholar
• Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J. Neurosci. 28, 6926–6937 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, W. H. et al. Macroautophagy — a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171, 87–98 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, S. et al. Rapamycin promotes β-amyloid production via ADAM-10 inhibition. Biochem. Biophys. Res. Commun. 398, 337–341 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ling, D., Song, H. J., Garza, D., Neufeld, T. P. & Salvaterra, P. M. Aβ42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila. PLoS ONE 4, e4201 (2009).
  Article PubMed PubMed Central Google Scholar
• Schols, L., Bauer, P., Schmidt, T., Schulte, T. & Riess, O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 3, 291–304 (2004).
  Article PubMed Google Scholar
• Menzies, F. M. et al. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93–104 (2010). In a genetic mouse model of spinocerebellar ataxia type 3, treatment with the rapamycin analogue temsirolimus reduces the number of ataxin-3-positive brain aggregates and improves motor performance by enhancing the autophagic degradation of toxic, mutant ataxin 3.
  Article CAS PubMed Google Scholar
• Pasinelli, P. & Brown, R. H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nature Rev. Neurosci. 7, 710–723 (2006).
  Article CAS Google Scholar
• Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
  Article CAS PubMed Google Scholar
• Zhang, X. et al. Rapamycin treatment augments motor neuron degeneration in SOD1 (G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412–425 (2011).
  Article CAS PubMed Google Scholar
• Kabuta, T., Suzuki, Y. & Wada, K. Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J. Biol. Chem. 281, 30524–30533 (2006).
  Article CAS PubMed Google Scholar
• Hetz, C. et al. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23, 2294–2306 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fornai, F. et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 105, 2052–2057 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Pizzasegola, C. et al. Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph. Lateral. Scler. 10, 221–228 (2009).
  Article CAS PubMed Google Scholar
• Gill, A., Kidd, J., Vieira, F., Thompson, K. & Perrin, S. No benefit from chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using a standard mouse model of familial ALS. PLoS ONE 4, e6489 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chio, A. et al. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 75, 619–625 (2010).
  Article CAS PubMed Google Scholar
• Chen-Plotkin, A. S., Lee, V. M. & Trojanowski, J. Q. TAR DNA-binding protein 43 in neurodegenerative disease. Nature Rev. Neurol. 6, 211–220 (2010).
  Article CAS Google Scholar
• Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
  Article CAS PubMed Google Scholar
• Gitcho, M. A. et al. TDP-43 A315T mutation in familial motor neuron disease. Ann. Neurol. 63, 535–538 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rutherford, N. J. et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 4, e1000193 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Caccamo, A. et al. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J. Biol. Chem. 284, 27416–27424 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Erlich, S., Alexandrovich, A., Shohami, E. & Pinkas-Kramarski, R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86–93 (2007).
  Article CAS PubMed Google Scholar
• Alirezaei, M., Kiosses, W. B., Flynn, C. T., Brady, N. R. & Fox, H. S. Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS ONE 3, e2906 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Carloni, S., Buonocore, G. & Balduini, W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 32, 329–339 (2008).
  Article CAS PubMed Google Scholar
• Zhao, C. et al. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J. Clin. Invest. 121, 369–383 (2011).
  Article CAS PubMed Google Scholar
• Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Medvedik, O., Lamming, D. W., Kim, K. D. & Sinclair, D. A. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 5, e261 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Alvers, A. L. et al. Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell 8, 353–369 (2009).
  Article CAS PubMed Google Scholar
• Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This article demonstrates that rapamycin is able to significantly extend lifespan in genetically heterogeneous mice of both sexes, even if these animals started the treatment late in life.
  Article CAS PubMed PubMed Central Google Scholar
• Anisimov, V. N. et al. Rapamycin extends maximal lifespan in cancer-prone mice. Am. J. Pathol. 176, 2092–2097 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kaeberlein, M., Burtner, C. R. & Kennedy, B. K. Recent developments in yeast aging. PLoS Genet. 3, e84 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).
  Article CAS PubMed Google Scholar
• Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).
  Article CAS PubMed Google Scholar
• Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Luong, N. et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 4, 133–142 (2006).
  Article CAS PubMed Google Scholar
• Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Bishop, N. A. & Guarente, L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nature Rev. Genet. 8, 835–844 (2007).
  Article CAS PubMed Google Scholar
• Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727–754 (2008).
  Article CAS PubMed Google Scholar
• Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).
  Article CAS PubMed Google Scholar
• Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, C. et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 205, 2397–2408 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex. Nature 450, 736–740 (2007).
  Article CAS PubMed Google Scholar
• Podbielski, J. & Schoenberg, L. Use of sirolimus in kidney transplantation. Prog. Transplant. 11, 29–32 (2001).
  Article CAS PubMed Google Scholar
• Kandzari, D. E. & Leon, M. B. Overview of pharmacology and clinical trials program with the zotarolimus-eluting endeavor stent. J. Interv. Cardiol. 19, 405–413 (2006).
  Article PubMed Google Scholar
• Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–918 (2004).
  Article CAS PubMed Google Scholar
• Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).
  Article CAS PubMed Google Scholar
• Massey, A. C., Kaushik, S., Sovak, G., Kiffin, R. & Cuervo, A. M. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 103, 5805–5810 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Sehgal, S. N., Baker, H. & Vezina, C. Rapamycin (AY-22989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. 28, 727–732 (1975).
  Article CAS Google Scholar
• Cloughesy, T. F. et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5, e8 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ekberg, H. et al. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study. Nephrol. Dial. Transplant. 25, 2004–2010 (2010).
  Article CAS PubMed Google Scholar
• Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).
  Article CAS PubMed Google Scholar
• Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Araki, K., Youngblood, B. & Ahmed, R. The role of mTOR in memory CD8 T-cell differentiation. Immunol. Rev. 235, 234–243 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Avellino, R. et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106, 1400–1406 (2005).
  Article CAS PubMed Google Scholar
• Tirado, O. M., Mateo-Lozano, S. & Notario, V. Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax: Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity. Oncogene 24, 3348–3357 (2005).
  Article CAS PubMed Google Scholar
• Swiech, L., Perycz, M., Malik, A. & Jaworski, J. Role of mTOR in physiology and pathology of the nervous system. Biochim. Biophys. Acta 1784, 116–132 (2008).
  Article CAS PubMed Google Scholar
• Hou, L. & Klann, E. Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 24, 6352–6361 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, S. J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl Acad. Sci. USA 99, 467–472 (2002).
  Article CAS PubMed Google Scholar
• Abel, T. & Lattal, K. M. Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11, 180–187 (2001).
  Article CAS PubMed Google Scholar
• Luzio, J. P., Pryor, P. R. & Bright, N. A. Lysosomes: fusion and function. Nature Rev. Mol. Cell Biol. 8, 622–632 (2007).
  Article CAS Google Scholar
• Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates autophagy. PLoS ONE 5, e15394 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
  Article CAS PubMed Google Scholar
• Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jung, C. H. et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ganley, I. G. et al. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J. Biol. Chem. 284, 12297–12305 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hara, T. et al. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J. Cell Biol. 181, 497–510 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 22, 132–139 (2010).
  Article CAS PubMed Google Scholar
• Peterson, T. R. et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137, 873–886 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).
  Article CAS PubMed Google Scholar
• Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
  Article CAS PubMed Google Scholar
• Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915 (2007).
  Article CAS PubMed Google Scholar
• Pearce, L. R. et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405, 513–522 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Frias, M. A. et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16, 1865–1870 (2006).
  Article CAS PubMed Google Scholar
• Yang, Q., Inoki, K., Ikenoue, T. & Guan, K. L. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 20, 2820–2832 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Yip, C. K., Murata, K., Walz, T., Sabatini, D. M. & Kang, S. A. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell 38, 768–774 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).
  Article CAS PubMed Google Scholar
• Narendra, D. P. & Youle, R. J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid. Redox Signal. 14, 1929–1938 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sulzer, D. et al. Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease. J. Neurochem. 106, 24–36 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).
  Article CAS PubMed Google Scholar