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Fighting neurodegeneration with rapamycin: mechanistic insights

Nature Reviews Neuroscience volume 12, pages 437–452 (2011)Cite this article

Subjects

Key Points

  • Multiple independent studies have recently shown that rapamycin, a US Food and Drug Administration (FDA)-approved antibiotic and immunosuppressant currently used to prevent rejection in organ transplantation, can provide therapeutic benefit in experimental models of several age-linked neurodegenerative diseases, including Parkinson's disease, Huntington's disease, Alzheimer's disease and spinocerebellar ataxia type 3.

  • Rapamycin is able to extend lifespan in various species, including mice, even when starting the treatment late in life.

  • Rapamycin inhibits the activity of mammalian target of rapamycin (mTOR), an intracellular serine/threonine protein kinase that is central in various cellular processes, including cell growth and proliferation, protein synthesis and autophagy. mTOR also has a key role in brain development and contributes to several functions in the adult normal brain, including synaptic plasticity, learning and memory.

  • Because of the multiplicity of mTOR downstream signalling pathways, different molecular mechanisms have been proposed to underlie rapamycin's neuroprotective effects in experimental models of neurodegeneration, such as induction of autophagy, decreased mitochondria-dependent apoptosis, blockade of cap-dependent translation of pro-cell death proteins and promotion of cap-independent translation of pro-survival factors. These mechanisms are not mutually exclusive and may act in concert to mediate the beneficial actions of rapamycin in neurodegeneration.

  • The potential therapeutic use of rapamycin, or some of its analogues, as disease-modifying agents in neurodegenerative conditions is discussed and possible limitations are taken into account, such as unfavourable physicochemical properties, undesirable side effects or potential alterations associated with chronic usage.

Abstract

A growing number of studies point to rapamycin as a pharmacological compound that is able to provide neuroprotection in several experimental models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3. In addition, rapamycin exerts strong anti-ageing effects in several species, including mammals. By inhibiting the activity of mammalian target of rapamycin (mTOR), rapamycin influences a variety of essential cellular processes, such as cell growth and proliferation, protein synthesis and autophagy. Here, we review the molecular mechanisms underlying the neuroprotective effects of rapamycin and discuss the therapeutic potential of this compound for neurodegenerative diseases.

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Figure 1: Composition and rapamycin-mediated regulation of mammalian target of rapamycin complexes.
Figure 2: Target of rapamycin signalling pathways.
Figure 3: Potential sites of rapamycin's therapeutic actions in experimental Parkinson's disease.

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References

  1. 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 

  2. 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 

  3. 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 

  4. 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 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nature Cell Biol. 13, 453–460 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Yamasaki, S. & Anderson, P. Reprogramming mRNA translation during stress. Curr. Opin. Cell Biol. 20, 222–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

  18. 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 

  19. 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 

  20. Wang, X. et al. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477–480 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. 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 

  24. 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 

  25. 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 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

  31. 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 

  32. 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 

  33. 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 

  34. 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 

  35. 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 

  36. 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 

  37. Wong, E. & Cuervo, A. M. Autophagy gone awry in neurodegenerative diseases. Nature Neurosci. 13, 805–811 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. 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 

  55. 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 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. 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 

  62. Pan, T. et al. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 164, 541–551 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Vila, M. & Przedborski, S. Genetic clues to the pathogenesis of Parkinson's disease. Nature Med. 10, S58–S62 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. 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 

  66. 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 

  67. 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 

  68. 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 

  69. Vila, M. & Przedborski, S. Targeting programmed cell death in neurodegenerative diseases. Nature Rev. Neurosci. 4, 365–375 (2003).

    Article  CAS  Google Scholar 

  70. 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 

  71. 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 

  72. 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 

  73. 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 

  74. 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 

  75. 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 

  76. 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 

  77. 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 

  78. 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 

  79. 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 

  80. 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 

  81. 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 

  82. 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 

  83. 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 

  84. 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 

  85. 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 

  86. 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 

  87. 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 

  88. 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 

  89. Garelick, M. G. & Kennedy, B. K. TOR on the brain. Exp. Gerontol. 46, 155–163 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. 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 

  95. Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. 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 

  97. 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 

  98. 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 

  99. 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 

  100. 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 

  101. 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 

  102. 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 

  103. 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 

  104. 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 

  105. 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 

  106. 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 

  107. 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 

  108. 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 

  109. 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 

  110. 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 

  111. 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 

  112. 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 

  113. 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 

  114. 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 

  115. 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 

  116. 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 

  117. 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 

  118. 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 

  119. 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 

  120. 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 

  121. 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 

  122. 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 

  123. 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 

  124. 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 

  125. 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 

  126. 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 

  127. 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 

  128. 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 

  129. 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 

  130. 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 

  131. 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 

  132. Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. 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 

  134. 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 

  135. 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 

  136. 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 

  137. 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 

  138. 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 

  139. Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. 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 

  141. 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 

  142. 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 

  143. Podbielski, J. & Schoenberg, L. Use of sirolimus in kidney transplantation. Prog. Transplant. 11, 29–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. 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 

  145. 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 

  146. 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 

  147. 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 

  148. 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 

  149. 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 

  150. 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 

  151. 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 

  152. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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 

  154. Avellino, R. et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106, 1400–1406 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. 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 

  156. 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 

  157. 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 

  158. 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 

  159. 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 

  160. 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 

  161. 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 

  162. 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 

  163. 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 

  164. 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 

  165. 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 

  166. 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 

  167. 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 

  168. 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 

  169. 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 

  170. 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 

  171. 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 

  172. 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 

  173. 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 

  174. 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 

  175. 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 

  176. 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 

  177. 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 

  178. 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 

  179. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the European Commission Marie Curie Excellence Grant (to M.V.), Marie Curie International Reintegration Grant (to M.V.), Fundació la Caixa, Spain (to M.V.), Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII), Spain (to M.V. and M.M-V.) Ministerio de Ciencia e Innovació (MICINN), Spain (to M.V. and M.M-V.) and Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Spain (to M.V.).

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Authors and Affiliations

  1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-CIBERNED, Barcelona, 08035, Spain

    Jordi Bové, Marta Martínez-Vicente & Miquel Vila

  2. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, 08010, Spain

    Miquel Vila

  3. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, 08193, Bellaterra, Spain

    Miquel Vila

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  1. Jordi Bové
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Correspondence to Miquel Vila.

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Supplementary information

Supplementary information S1 (table)

Effects of rapamycin in Parkinson's disease-related experimental in vitro models (PDF 351 kb)

Supplementary information S2 (table)

Effects of rapamycin in Huntington's disease-related experimental in vitro models (PDF 328 kb)

Supplementary information S3 (table)

Effects of rapamycin in other experimental in vitro models of neurodegeneration (PDF 321 kb)

Supplementary information S4 (table)

Effects of rapamycin on aging (PDF 286 kb)

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DATABASES

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Glossary

Cap-dependent translation

A form or mRNA translation in which a nuclear modification at the 5′ end of eukaryotic mRNAs, called the cap structure, acts as a tag for the recruitment of the 40S ribosomal subunit and the eukaryotic translation initiation factor 4F (eIF4F) complex to initiate translation.

AGC kinases

A subfamily of serine/threonine protein kinases that, based on sequence alignments of their catalytic kinase domain, are related to cyclic AMP-dependent protein kinase 1 (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC). AGC kinases control critical cellular processes, such as cell growth, differentiation and cell survival, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.

MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). MPTP is a by-product of the chemical synthesis of a meperidine analogue with potent heroin-like effects that causes in humans a syndrome mimicking the core neurological symptoms and relatively selective dopaminergic neurodegeneration of Parkinson's disease. In primates and mice, MPTP kills dopaminergic neurons and has been extensively used to model dopaminergic neurodegeneration linked to Parkinson's disease.

6-OHDA

6-OHDA is a noradrenergic analogue that triggers dopaminergic neurodegeneration when administered directly into the nigrostriatal system of rodents.

MPP+

(1-methyl-4-phenylpyridinium). The active metabolite of MPTP. MPTP is a pro-toxin that after crossing the blood–brain barrier is metabolized into 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) by the enzyme monoamine oxidase B (MAO-B) in non-dopaminergic cells and then, probably by spontaneous oxidation, to MPP+. MPP+ enters dopaminergic neurons through dopamine transporters, for which it has high affinity, and is concentrated by an active process within the mitochondria, where it impairs mitochondrial respiration by inhibiting complex I of the electron transport chain.

Rotenone

An inhibitor of mitochondrial complex I that is widely used as an insecticide and piscicide. In rodents, intravenous and subcutaneous infusion of rotenone produces nigrostriatal dopaminergic neurodegeneration, loss of intrinsic striatal neurons and formation of proteinaceous inclusions.

Paraquat

A herbicide that induces dopaminergic cell loss and α-synuclein accumulations in rodents when administered systemically.

3-NP

(3-nitro-propionic acid). An inhibitor of mitochondrial complex II of the electron transport chain that is used to mimic striatal lesions linked to Huntington's disease.

Light-gathering rhabdomeres

The compound eye of Drosophila spp. comprises many units, called ommatidia, each containing eight photoreceptor neurons with light-gathering parts called rhabdomeres.

R6/2 model of Huntington's disease

(HDQ150 mice). Transgenic mice (strain of origin CBA × C57BL/6) for the 5′ end of the human Huntington's disease gene carrying approximately 160 ± 10 glutamines. Mice exhibit a progressive neurological phenotype that mimics many features of Huntington's disease.

Beclin 1

Mammalian beclin 1 (known as autophagy-related protein 6 (Atg6) or vacuolar protein sorting-associated protein 30 (Vps30) in yeast) is a protein involved in autophagic vesicle nucleation. It associates with several other proteins, such as Vps34 or Vps15 in yeast and activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) or UV radiation resistance-associated gene protein (UVRAG) in mammals, to form a protein complex that initiates the formation of the autophagosome.

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Bové, J., Martínez-Vicente, M. & Vila, M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 12, 437–452 (2011). https://doi.org/10.1038/nrn3068

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