NeuroMolecular Medicine

, Volume 19, Issue 1, pp 1–10 | Cite as

mTOR Signaling in Parkinson’s Disease

  • Ai-ping Lan
  • Jun Chen
  • Yuliang Zhao
  • Zhifang Chai
  • Yi Hu
Review Paper

Abstract

As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson’s disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.

Keywords

mTOR Parkinson’s disease Apoptosis α-Synuclein Oxidative stress 

References

  1. Anderson, G., & Maes, M. (2014). Neurodegeneration in Parkinson’s disease: interactions of oxidative stress, tryptophan catabolites and depression with mitochondria and sirtuins. Molecular Neurobiology, 49, 771–783.PubMedCrossRefGoogle Scholar
  2. Anglade, P., et al. (1997). Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histology and Histopathology, 12, 25–31.PubMedGoogle Scholar
  3. Bao, X. Q., et al. (2012). FLZ protects dopaminergic neuron through activating protein kinase B/mammalian target of rapamycin pathway and inhibiting RTP801 expression in Parkinson’s disease models. Neuroscience, 202, 396–404.PubMedCrossRefGoogle Scholar
  4. Bjedov, I., et al. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metabolism, 11, 35–46.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bockaert, J., & Marin, P. (2015). mTOR in brain physiology and pathologies. Physiological Reviews, 95, 1157–1187.PubMedCrossRefGoogle Scholar
  6. Boland, D. F., & Stacy, M. (2012). The economic and quality of life burden associated with Parkinson’s disease: A focus on symptoms. The American Journal of Managed Care, 18, S168–S175.PubMedGoogle Scholar
  7. Cannon, J. R., et al. (2013). Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson’s disease features and enhances vulnerability to mitochondrial impairment. Experimental Neurology, 240, 44–56.PubMedCrossRefGoogle Scholar
  8. Cartier, A. E., et al. (2012). Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy. PLoS ONE, 7, e34713.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chen, L., et al. (2008). MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. Journal of Neurochemistry, 105, 251–261.PubMedCrossRefGoogle Scholar
  10. Chen, L., et al. (2010). Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Laboratory Investigation, 90, 762–773.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chen, L., et al. (2011). Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radical Biology & Medicine, 50, 624–632.CrossRefGoogle Scholar
  12. Chen, L. L., et al. (2014). Corynoxine, a natural autophagy enhancer, promotes the clearance of alpha-synuclein via Akt/mTOR pathway. Journal of Neuroimmune Pharmacology, 9, 380–387.PubMedCrossRefGoogle Scholar
  13. Cheung, Z. H., & Ip, N. Y. (2011). Autophagy deregulation in neurodegenerative diseases—Recent advances and future perspectives. Journal of Neurochemistry, 118, 317–325.PubMedCrossRefGoogle Scholar
  14. Choi, K. C., et al. (2010). A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. Journal of Neurochemistry, 112, 366–376.PubMedCrossRefGoogle Scholar
  15. Chong, Z. Z., et al. (2012). PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. PLoS ONE, 7, e45456.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Choo, A. Y., et al. (2008). Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proceedings of the National Academy of Sciences of the United States of America, 105, 17414–17419.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chu, Y., et al. (2009). Alterations in lysosomal and proteasomal markers in Parkinson’s disease: Relationship to alpha-synuclein inclusions. Neurobiology of Diseases, 35, 385–398.CrossRefGoogle Scholar
  18. Ciccone, S., et al. (2013). Parkinson’s disease: A complex interplay of mitochondrial DNA alterations and oxidative stress. International Journal of Molecular Sciences, 14, 2388–2409.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. Current Opinion in Genetics & Development, 23, 53–62.CrossRefGoogle Scholar
  20. Crews, L., et al. (2010). Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE, 5, e9313.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cuervo, A. M., et al. (2005). Autophagy and aging: The importance of maintaining “clean” cells. Autophagy, 1, 131–140.PubMedCrossRefGoogle Scholar
  22. Cullen, V., et al. (2011). Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Annals of Neurology, 69, 940–953.PubMedCrossRefGoogle Scholar
  23. Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: Mechanisms and models. Neuron, 39, 889–909.PubMedCrossRefGoogle Scholar
  24. Dawson, T. M., & Dawson, V. L. (2003). Molecular pathways of neurodegeneration in Parkinson’s disease. Science, 302, 819–822.PubMedCrossRefGoogle Scholar
  25. Decressac, M., & Bjorklund, A. (2013). mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats. Journal of Parkinsons Disease, 3, 13–17.Google Scholar
  26. Decressac, M., et al. (2013). TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proceedings of the National Academy of Sciences of the United States of America, 110, E1817–E1826.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Dehay, B., et al. (2010). Pathogenic lysosomal depletion in Parkinson’s disease. Journal of Neuroscience, 30, 12535–12544.PubMedCrossRefGoogle Scholar
  28. Dehay, B., et al. (2015). Targeting α-synuclein for treatment of Parkinson’s disease: Mechanistic and therapeutic considerations. Lancet Neurology, 14, 855–866.PubMedCrossRefGoogle Scholar
  29. Dennis, M. D., Kimball, S. R., & Jefferson, L. S. (2013). Mechanistic target of rapamycin complex 1 (mTORC1)-mediated phosphorylation is governed by competition between substrates for interaction with raptor. Journal of Biological Chemistry, 288, 10–19.PubMedCrossRefGoogle Scholar
  30. Dexter, D. T., & Jenner, P. (2013). Parkinson disease: From pathology to molecular disease mechanisms. Free Radical Biology and Medicine, 62, 132–144.PubMedCrossRefGoogle Scholar
  31. DeYoung, M. P., et al. (2008). Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes & Development, 22, 239–251.CrossRefGoogle Scholar
  32. Dijkstra, A. A., et al. (2015). Evidence for immune response, axonal dysfunction and reduced endocytosis in the substantia nigra in early stage Parkinson’s disease. PLoS ONE, 10, e0128651.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Domanskyi, A., et al. (2011). Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models. FASEB Journal, 25, 2898–2910.PubMedCrossRefGoogle Scholar
  34. Francois, A., et al. (2014). Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice. Molecular Brain, 7, 56.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Frias, M. A., et al. (2006). mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Current Biology, 16, 1865–1870.PubMedCrossRefGoogle Scholar
  36. Gao, X., et al. (2002). Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biology, 4, 699–704.PubMedCrossRefGoogle Scholar
  37. Garcia-Martinez, J. M., & Alessi, D. R. (2008). mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochemical Journal, 416, 375–385.PubMedCrossRefGoogle Scholar
  38. Guertin, D. A., et al. (2006). Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Developmental Cell, 11, 859–871.PubMedCrossRefGoogle Scholar
  39. Gulhati, P., et al. (2011). mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Research, 71, 3246–3256.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Gumy, L. F., Tan, C. L., & Fawcett, J. W. (2010). The role of local protein synthesis and degradation in axon regeneration. Experimental Neurology, 223, 28–37.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Ha, J. Y., et al. (2014). Tnfaip8l1/Oxi-beta binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson’s disease model. Journal of Neurochemistry, 129, 527–538.PubMedCrossRefGoogle Scholar
  42. Hara, T., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441, 885–889.PubMedCrossRefGoogle Scholar
  43. He, C., et al. (2013). Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes, 62, 1270–1281.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Hu, Y., & Tong, Y. (2010). A trojan horse for Parkinson’s disease. Science Signaling, 3, pe13.PubMedCrossRefGoogle Scholar
  45. Huang, J., et al. (2008). The TSC1–TSC2 complex is required for proper activation of mTOR complex 2. Molecular and Cellular Biology, 28, 4104–4115.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Huang, J., et al. (2009). Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Research, 69, 6107–6114.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hussain, S., et al. (2013). Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor. Molecular and Cellular Biology, 33, 1188–1197.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Imai, Y., et al. (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO Journal, 27, 2432–2443.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Inoki, K., Zhu, T., & Guan, K. L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell, 115, 577–590.PubMedCrossRefGoogle Scholar
  50. Inoki, K., et al. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology, 4, 648–657.PubMedCrossRefGoogle Scholar
  51. Jacinto, E., et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology, 6, 1122–1128.PubMedCrossRefGoogle Scholar
  52. Jaworski, J., & Sheng, M. (2006). The growing role of mTOR in neuronal development and plasticity. Molecular Neurobiology, 34, 205–219.PubMedCrossRefGoogle Scholar
  53. Jayaram, H. N., Kusumanchi, P., & Yalowitz, J. A. (2011). NMNAT expression and its relation to NAD metabolism. Current Medicinal Chemistry, 18, 1962–1972.PubMedCrossRefGoogle Scholar
  54. Jeong, J. K., et al. (2012). Autophagy induced by resveratrol prevents human prion protein-mediated neurotoxicity. Neuroscience Research, 73, 99–105.PubMedCrossRefGoogle Scholar
  55. Jiang, J., et al. (2013a). Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson’s disease. International Journal of Molecular Medicine, 31, 825–832.PubMedGoogle Scholar
  56. Jiang, T. F., et al. (2013b). Curcumin ameliorates the neurodegenerative pathology in A53T α-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. Journal of Neuroimmune Pharmacology, 8, 356–369.PubMedCrossRefGoogle Scholar
  57. Kahn, B. B., et al. (2005). AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism, 1, 15–25.PubMedCrossRefGoogle Scholar
  58. Kim, S. R., et al. (2011). Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration. Annals of Neurology, 70, 110–120.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kim, H. J., et al. (2014a). Neuroprotective effect of chebulagic acid via autophagy induction in SH-SY5Y cells. Biomolecules & Therapeutics (Seoul), 22, 275–281.CrossRefGoogle Scholar
  60. Kim, K. A., et al. (2014b). High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment. Biological and Pharmaceutical Bulletin, 37, 1248–1252.PubMedCrossRefGoogle Scholar
  61. Kim, C., et al. (2015). Antagonizing neuronal toll-like receptor 2 prevents synucleinopathy by activating autophagy. Cell Reports, 13, 771–782.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Komatsu, M., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature, 441, 880–884.PubMedCrossRefGoogle Scholar
  63. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149, 274–293.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lim, Y. M., et al. (2014). Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nature Communications, 5, 4934.PubMedCrossRefGoogle Scholar
  65. Lin, X., et al. (2012). Conditional expression of Parkinson’s disease-related mutant a-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. Journal of Neuroscience, 32, 9248–9264.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Loewith, R., et al. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular Cell, 10, 457–468.PubMedCrossRefGoogle Scholar
  67. Ma, X. M., & Blenis, J. (2009). Molecular mechanisms of mTOR-mediated translational control. Nature Reviews Molecular Cell Biology, 10, 307–318.PubMedCrossRefGoogle Scholar
  68. Magri, L., et al. (2011). Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell, 9, 447–462.PubMedCrossRefGoogle Scholar
  69. Maiese, K. (2015). Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Current Neurovascular Research, 12, 173–188.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Maiese, K., et al. (2010). Oxidative stress: Biomarkers and novel therapeutic pathways. Experimental Gerontology, 45, 217–234.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Maiese, K., et al. (2013). mTOR: On target for novel therapeutic strategies in the nervous system. Trends in Molecular Medicine, 19, 51–60.PubMedCrossRefGoogle Scholar
  72. Malagelada, C., Jin, Z. H., & Greene, L. A. (2008). RTP801 is induced in Parkinson’s disease and mediates neuron death by inhibiting Akt phosphorylation/activation. Journal of Neuroscience, 28, 14363–14371.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Malagelada, C., et al. (2006). 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. Journal of Neuroscience, 26, 9996–10005.PubMedCrossRefGoogle Scholar
  74. Malagelada, C., et al. (2010). Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. Journal of Neuroscience, 30, 1166–1175.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Manning, B. D., & Cantley, L. C. (2003). Rheb fills a GAP between TSC and TOR. Trends in Biochemical Sciences, 28, 573–576.PubMedCrossRefGoogle Scholar
  76. Menzies, F. M., Fleming, A., & Rubinsztein, D. C. (2015). Compromised autophagy and neurodegenerative diseases. Nature Reviews Neuroscience, 16, 345–357.PubMedCrossRefGoogle Scholar
  77. Murata, H., et al. (2011). A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: Activation of AKT via mTORC2. Journal of Biological Chemistry, 286, 7182–7189.PubMedCrossRefGoogle Scholar
  78. Mythri, R. B., et al. (2011). Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson’s disease brains. Neurochemical Research, 36, 1452–1463.PubMedCrossRefGoogle Scholar
  79. Nakka, V. P., Prakash-Babu, P., & Vemuganti, R. (2016). Crosstalk between endoplasmic reticulum stress, oxidative stress, and autophagy: Potential therapeutic targets for acute CNS injuries. Molecular Neurobiology, 53, 532–544.PubMedCrossRefGoogle Scholar
  80. Nordstrom, U., et al. (2015). Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiology of Diseases, 73, 70–82.CrossRefGoogle Scholar
  81. Oh, W. J., & Jacinto, E. (2011). mTOR complex 2 signaling and functions. Cell Cycle, 10, 2305–2316.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Pan, T., et al. (2008). Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiology of Diseases, 32, 16–25.CrossRefGoogle Scholar
  83. Pan, T., et al. (2009). Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience, 164, 541–551.PubMedCrossRefGoogle Scholar
  84. Panov, A., et al. (2005). Rotenone model of Parkinson disease: Multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. Journal of Biological Chemistry, 280, 42026–42035.PubMedCrossRefGoogle Scholar
  85. Pearce, L. R., et al. (2011). Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochemical Journal, 436, 169–179.PubMedCrossRefGoogle Scholar
  86. Perez-Revuelta, B. I., et al. (2014). Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death and Disease, 5, e1209.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Perier, C., et al. (2003). The rotenone model of Parkinson’s disease. Trends in Neurosciences, 26, 345–346.PubMedCrossRefGoogle Scholar
  88. Perier, C., et al. (2005). Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proceedings of the National Academy of Sciences of the United States of America, 102, 19126–19131.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Peterson, T. R., et al. (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137, 873–886.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Ravikumar, B., et al. (2006). Rapamycin pre-treatment protects against apoptosis. Human Molecular Genetics, 15, 1209–1216.PubMedCrossRefGoogle Scholar
  91. Richardson, J. R., et al. (2005). Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicological Sciences, 88, 193–201.PubMedCrossRefGoogle Scholar
  92. Rieker, C., et al. (2011). Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling. Journal of Neuroscience, 31, 453–460.PubMedCrossRefGoogle Scholar
  93. Rodriguez-Blanco, J., et al. (2012). Cooperative action of JNK and AKT/mTOR in 1-methyl-4-phenylpyridinium-induced autophagy of neuronal PC12 cells. Journal of Neuroscience Research, 90, 1850–1860.PubMedCrossRefGoogle Scholar
  94. Romani-Aumedes, J., et al. (2014). Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson’s disease. Cell Death and Disease, 5, e1364.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Ruffels, J., Griffin, M., & Dickenson, J. M. (2004). Activation of ERK1/2, JNK and PKB by hydrogen peroxide in human SH-SY5Y neuroblastoma cells: role of ERK1/2 in H2O2-induced cell death. European Journal of Pharmacology, 483, 163–173.PubMedCrossRefGoogle Scholar
  96. Santini, E., et al. (2009). Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Science Signaling, 2, 36.CrossRefGoogle Scholar
  97. Sarbassov, D. D., et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology, 14, 1296–1302.PubMedCrossRefGoogle Scholar
  98. Sarbassov, D. D., et al. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell, 22, 159–168.PubMedCrossRefGoogle Scholar
  99. Sarkar, S., et al. (2005). Lithium induces autophagy by inhibiting inositol monophosphatase. Journal of Cell Biology, 170, 1101–1111.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Sarkar, S., et al. (2007). Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. Journal of Biological Chemistry, 282, 5641–5652.PubMedCrossRefGoogle Scholar
  101. Schapira, A. H., et al. (2014). Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: Future therapeutic perspectives. Lancet, 384, 545–555.PubMedCrossRefGoogle Scholar
  102. Selvaraj, S., et al. (2012). Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. The Journal of Clinical Investigation, 122, 1354–1367.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Shang, Y. C., et al. (2011). Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia. Current Neurovascular Research, 8, 270–285.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Shang, Y. C., et al. (2012a). Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging, 4, 187–201.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Shang, Y. C., et al. (2012b). Wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern beta-amyloid apoptotic injury of microglia. Current Neurovascular Research, 9, 239–249.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Shulman, J. M., De Jager, P. L., & Feany, M. B. (2011). Parkinson’s disease: Genetics and pathogenesis. Annual Review of Pathology: Mechanisms of Disease, 6, 193–222.CrossRefGoogle Scholar
  107. Silva, D. F., et al. (2011). Mitochondria: the common upstream driver of amyloid-beta and tau pathology in Alzheimer’s disease. Current Alzheimer Research, 8, 563–572.PubMedCrossRefGoogle Scholar
  108. Spencer, B., et al. (2009). Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. Journal of Neuroscience, 29, 13578–13588.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Subramaniam, S., et al. (2012). Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nature Neuroscience, 15, 191–193.CrossRefGoogle Scholar
  110. Swiech, L., et al. (2008). Role of mTOR in physiology and pathology of the nervous system. Biochimica et Biophysica Acta, 1784, 116–132.PubMedCrossRefGoogle Scholar
  111. Tain, L. S., et al. (2009). Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience, 12, 1129–1135.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Tee, A. R., et al. (2002). Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proceedings of the National Academy of Sciences of the United States of America, 99, 13571–13576.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Thoreen, C. C., & Sabatini, D. M. (2009). Rapamycin inhibits mTORC1, but not completely. Autophagy, 5, 725–726.PubMedCrossRefGoogle Scholar
  114. Thoreen, C. C., et al. (2009). An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. Journal of Biological Chemistry, 284, 8023–8032.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Tieu, K. (2011). A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harbor Perspectives in Medicine, 1, a009316.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Vakifahmetoglu-Norberg, H., Xia, H. G., & Yuan, J. (2015). Pharmacologic agents targeting autophagy. Journal of Clinical Investigation, 125, 5–13.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Vila, M., et al. (2011). Lysosomal membrane permeabilization in Parkinson disease. Autophagy, 7, 98–100.PubMedCrossRefGoogle Scholar
  118. Wang, H., et al. (2012a). Proline-rich Akt substrate of 40 kDa (PRAS40): A novel downstream target of PI3 k/Akt signaling pathway. Cellular Signalling, 24, 17–24.PubMedCrossRefGoogle Scholar
  119. Wang, Y., et al. (2012b). Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells. American Journal of Translational Research, 4, 44–51.PubMedPubMedCentralGoogle Scholar
  120. Webb, J. L., et al. (2003). Alpha-synuclein is degraded by both autophagy and the proteasome. Journal of Biological Chemistry, 278, 25009–25013.PubMedCrossRefGoogle Scholar
  121. Williams, A. C., et al. (2012). Nicotinamide, NAD(P)(H), and methyl-group homeostasis evolved and became a determinant of ageing diseases: Hypotheses and lessons from pellagra. Current Gerontology and Geriatrics Research, 2012, 302875.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Wills, J., et al. (2012). Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PLoS ONE, 7, e30745.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Wong, E., & Cuervo, A. M. (2010). Autophagy gone awry in neurodegenerative diseases. Nature Neuroscience, 13, 805–811.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Wu, A. G., et al. (2013). Onjisaponin B derived from Radix Polygalae enhances autophagy and accelerates the degradation of mutant a-synuclein and huntingtin in PC-12 cells. International Journal of Molecular Sciences, 14, 22618–22641.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124, 471–484.PubMedCrossRefGoogle Scholar
  126. Xiong, X., et al. (2014). PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways. Neurobiology of Diseases, 66, 43–52.CrossRefGoogle Scholar
  127. Xu, B., et al. (2011). Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network. PLoS ONE, 6, e19052.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Xu, Y., et al. (2014). Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cellular Signalling, 26, 1680–1689.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Yacoubian, T. A., & Standaert, D. G. (2009). Targets for neuroprotection in Parkinson’s disease. Biochimica et Biophysica Acta, 1792, 676–687.PubMedCrossRefGoogle Scholar
  130. Yamada, E., & Singh, R. (2012). Mapping autophagy on to your metabolic radar. Diabetes, 61, 272–280.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Yan, J. Q., et al. (2014). Overexpression of human E46K mutant a-synuclein impairs macroautophagy via inactivation of JNK1-Bcl-2 pathway. Molecular Neurobiology, 50, 685–701.PubMedCrossRefGoogle Scholar
  132. Yang, H., et al. (2011). Oxidative stress and diabetes mellitus. Clinical Chemistry and Laboratory Medicine, 49, 1773–1782.PubMedGoogle Scholar
  133. Yu, W. H., et al. (2009). Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. American Journal of Pathology, 175, 736–747.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Zeng, X. S., et al. (2014). The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radical Biology and Medicine, 67, 10–18.PubMedCrossRefGoogle Scholar
  135. Zhang, Z., et al. (2015). Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease. Free Radical Biology and Medicine, 84, 331–343.PubMedCrossRefGoogle Scholar
  136. Zhou, Q., et al. (2015). Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis. Toxicological Sciences, 143, 81–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ai-ping Lan
    • 1
  • Jun Chen
    • 1
  • Yuliang Zhao
    • 1
  • Zhifang Chai
    • 1
  • Yi Hu
    • 1
  1. 1.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Multi-disciplinary Research Division, Institute of High Energy PhysicsChinese Academy of Sciences (CAS)BeijingChina

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