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Activating Autophagy as a Therapeutic Strategy for Parkinson’s Disease

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A Letter to the Editor to this article was published on 27 June 2018

Abstract

Parkinson’s disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson’s disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson’s disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson’s disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in α-synuclein Parkinson’s disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson’s disease and yields promising results in clinical trials.

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References

  1. Lonskaya I, Hebron ML, Desforges NM, et al. Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013;5(8):1247–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22(16):3315–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hebron ML, Lonskaya I, Moussa CE. Tyrosine kinase inhibition facilitates autophagic SNCA/alphasynuclein clearance. Autophagy. 2013;9(8):1249–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Seglen PO. Regulation of autophagic protein degradation in isolated liver cells. In: Glaumann H, Ballard FJ, editors. Lysosomes: their role in protein breakdown. London: Academic; 1987. p. 369–414.

    Google Scholar 

  6. de Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.

    Article  PubMed  Google Scholar 

  7. Dunn WA Jr. Autophagy and related mechanisms of lysosome-mediated protein degradation. Trends Cell Biol. 1994;4(4):139–43.

    Article  PubMed  CAS  Google Scholar 

  8. Gordon PB, Seglen PO. Prelysosomal convergence of autophagic and endocytic pathways. Biochem Biophys Res Commun. 1988;151(1):40–7.

    Article  PubMed  CAS  Google Scholar 

  9. Macintosh RL, Ryan KM. Autophagy in tumour cell death. Semin Cancer Biol. 2013;23(5):344–51.

    Article  PubMed  CAS  Google Scholar 

  10. Crighton D, Wilkinson S, O’Prey J, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126(1):121–34.

    Article  PubMed  CAS  Google Scholar 

  11. Yee KS, Wilkinson S, James J, et al. PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ. 2009;16(8):1135–45.

    Article  PubMed  CAS  Google Scholar 

  12. Mellman I. Endocytosis and molecular sorting. Annu Rev Cell Dev Biol. 1996;12:575–625.

    Article  PubMed  CAS  Google Scholar 

  13. Jerram AH, Smith PF, Darlington CL. A dose-response analysis of the behavioral effects of (+)MK-801 in guinea pig: comparison with CPP. Pharmacol Biochem Behav. 1996;53(4):799–807.

    Article  PubMed  CAS  Google Scholar 

  14. Luzio JP, Rous BA, Bright NA, et al. Lysosome-endosome fusion and lysosome biogenesis. J Cell Sci. 2000;113(Pt 9):1515–24.

    PubMed  CAS  Google Scholar 

  15. Alexopoulou Z, Lang J, Perrett RM, et al. Deubiquitinase Usp8 regulates alpha-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci USA. 2016;113(32):E4688–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Deger JM, Gerson JE, Kayed R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell. 2015;14(5):715–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sugeno N, Hasegawa T, Tanaka N, et al. Lys-63-linked ubiquitination by E3 ubiquitin ligase Nedd4-1 facilitates endosomal sequestration of internalized alphasynuclein. J Biol Chem. 2014;289(26):18137–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ciechanover A, Kwon YT. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med. 2015;47:e147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Cuervo AM, Stefanis L, Fredenburg R, et al. Impaired degradation of mutant alphasynuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292–5.

    Article  PubMed  CAS  Google Scholar 

  20. Martinez-Vicente M, Talloczy Z, Kaushik S, et al. Dopaminemodified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest. 2008;118(2):777–88.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Xilouri M, Vogiatzi T, Vekrellis K, et al. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One. 2009;4(5):e5515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Boland B, Kumar A, Lee S, et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci. 2008;28(27):6926–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Kegel KB, Kim M, Sapp E, et al. Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci. 2000;20(19):7268–78.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64(2):113–22.

    Article  PubMed  Google Scholar 

  25. Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet. 2002;11(9):1107–17.

    Article  PubMed  CAS  Google Scholar 

  26. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34.

    Article  PubMed  CAS  Google Scholar 

  27. Stefanis L, Larsen KE, Rideout HJ, et al. Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci. 2001;21(24):9549–60.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Webb JL, Ravikumar B, Atkins J, et al. Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278(27):25009–13.

    Article  PubMed  CAS  Google Scholar 

  29. Yang Y, Fukui K, Koike T, et al. Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur J Neurosci. 2007;26(10):2979–88.

    Article  PubMed  Google Scholar 

  30. Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular selfdigestion. Nature. 2008;451(7182):1069–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Nixon RA, Yang DS, Lee JH. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy. 2008;4(5):590–9.

    Article  PubMed  CAS  Google Scholar 

  32. Winslow AR, Rubinsztein DC. Autophagy in neurodegeneration and development. Biochim Biophys Acta. 2008;1782(12):723–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Lee JH, Yu WH, Kumar A, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Yu WH, Cuervo AM, Kumar A, et al. Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol. 2005;171(1):87–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kaasik A, Rikk T, Piirsoo A, et al. Up-regulation of lysosomal cathepsin L and autophagy during neuronal death induced by reduced serum and potassium. Eur J Neurosci. 2005;22(5):1023–31.

    Article  PubMed  Google Scholar 

  36. Pan T, Kondo S, Le W, et al. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain. 2008;131(Pt 8):1969–78.

    Article  PubMed  Google Scholar 

  37. Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585–95.

    Article  PubMed  CAS  Google Scholar 

  38. Sarkar S, Perlstein EO, Imarisio S, et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol. 2007;3(6):331–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lonskaya I, Hebron ML, Algarzae NK, et al. Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease. Neuroscience. 2013;232:90–105.

    Article  PubMed  CAS  Google Scholar 

  40. Lonskaya I, Desforges NM, Hebron ML, et al. Ubiquitination increases parkin activity to promote autophagic alpha-synuclein clearance. PLoS One. 2013;8(12):e83914.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Illi B, Dello Russo C, Colussi C, et al. Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling. Circ Res. 2008;102(1):51–8.

    Article  PubMed  CAS  Google Scholar 

  42. Martin M, Potente M, Janssens V, et al. Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis. Proc Natl Acad Sci USA. 2008;105(12):4727–32.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Simboeck E, Sawicka A, Zupkovitz G, et al. A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors. J Biol Chem. 2010.

  44. Vingtdeux V, Chandakkar P, Zhao H, et al. Novel synthetic small molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. FASEB J. 2010.

  45. Khandelwal PJ, Herman AM, Hoe HS, et al. Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet. 2011;20(11):2091–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Herman AM, Moussa CE. The ubiquitin ligase parkin modulates the execution of autophagy. Autophagy. 2011;7(8):919–21.

    Article  PubMed  Google Scholar 

  47. Wong ES, Tan JM, Soong WE, et al. Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet. 2008;17(16):2570–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Pickford F, Masliah E, Britschgi M, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008;118(6):2190–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  50. Spencer B, Potkar R, Trejo M, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci. 2009;29(43):13578–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Adler CH, Beach TG, Shill HA, et al. GBA mutations in Parkinson disease: earlier death but similar neuropathological features. Eur J Neurol. 2017.

  52. O’Regan G, deSouza RM, Balestrino R, et al. Glucocerebrosidase Mutations in Parkinson Disease. J Parkinsons Dis. 2017;7(3):411–22.

    Article  PubMed  CAS  Google Scholar 

  53. Abeliovich A, Gitler AD. Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature. 2016;539(7628):207–16.

    Article  PubMed  Google Scholar 

  54. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46(9):989–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Eskelinen E-L. Maturation of autophagic vacuoles in mammalian cells. Autophagy. 2005;1(1):1–10.

    Article  PubMed  CAS  Google Scholar 

  56. Kirkin V, McEwan DG, Novak I, et al. A role for ubiquitin in selective autophagy. Mol Cell. 2009;34(3):259–69.

    Article  PubMed  CAS  Google Scholar 

  57. Sarkar S, Ravikumar B, Rubinsztein DC. Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol. 2009;453:83–110.

    Article  PubMed  CAS  Google Scholar 

  58. Bjorkoy G, Lamark T, Brech A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171(4):603–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Tan JM, Wong ES, Dawson VL, et al. Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy. 2007;4(2):251–3.

    Article  Google Scholar 

  60. Iwata A, Riley BE, Johnston JA, et al. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem. 2005;280(48):40282–92.

    Article  PubMed  CAS  Google Scholar 

  61. Cheong H, Nair U, Geng J, et al. The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell. 2008;19(2):668–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Geng J, Baba M, Nair U, et al. Quantitative analysis of autophagy-related protein stoichiometry by fluorescence microscopy. J Cell Biol. 2008;182(1):129–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Fukuda M, Itoh T. Direct link between Atg protein and small GTPase Rab: Atg16L functions as a potential Rab33 effector in mammals. Autophagy. 2008;4(6):824–6.

    Article  PubMed  CAS  Google Scholar 

  64. Hosokawa N, Sasaki T, Iemura S, et al. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy. 2009;5(7):973–9.

    Article  PubMed  CAS  Google Scholar 

  65. Nair U, Cao Y, Xie Z, et al. Roles of the lipid-binding motifs of Atg18 and Atg21 in the cytoplasm to vacuole targeting pathway and autophagy. J Biol Chem. 2010;285(15):11476–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Geng J, Klionsky DJ. Determining Atg protein stoichiometry at the phagophore assembly site by fluorescence microscopy. Autophagy. 2010;6(1):144–7.

    Article  PubMed  CAS  Google Scholar 

  67. Mizushima N, Yamamoto A, Matsui M, et al. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15(3):1101–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Huang W-P, Scott SV, Kim J, et al. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem. 2000;275(8):5845–51.

    Article  PubMed  CAS  Google Scholar 

  69. Kovacs AL, Reith A, Seglen PO. Accumulation of autophagosomes after inhibition of hepatocytic protein degradation by vinblastine, leupeptin or a lysosomotropic amine. Exp Cell Res. 1982;137(1):191–201.

    Article  PubMed  CAS  Google Scholar 

  70. Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302–5.

    Article  PubMed  CAS  Google Scholar 

  71. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392(6676):605–8.

    Article  PubMed  CAS  Google Scholar 

  72. Lucking CB, Durr A, Bonifati V, et al. Association between earlyonset Parkinson’s disease and mutations in the parkin gene. N Engl J Med. 2000;342(21):1560–7.

    Article  PubMed  CAS  Google Scholar 

  73. Imam SZ, Zhou Q, Yamamoto A, et al. Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson’s disease. J Neurosci. 2011;31(1):157–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Ko HS, Lee Y, Shin JH, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits Parkin’s ubiquitination and protective function. Proc Natl Acad Sci USA. 2010;107(38):16691–6.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Rosen KM, Moussa CE, Lee HK, et al. Parkin reverses intracellular betaamyloid accumulation and its negative effects on proteasome function. J Neurosci Res. 2010;88(1):167–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Moussa CE. Parkin attenuates wild-type tau modification in the presence of beta-amyloid and alphasynuclein. J Mol Neurosci. 2009;37(1):25–36.

    Article  PubMed  CAS  Google Scholar 

  77. Khandelwal PJ, Dumanis SB, Feng LR, et al. Parkinson-related parkin reduces alpha-Synuclein phosphorylation in a gene transfer model. Mol Neurodegener. 2010;5:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Rodriguez-Navarro JA, Rodriguez L, Casarejos MJ, et al. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis. 2010;39(3):423–38.

    Article  PubMed  CAS  Google Scholar 

  79. Geisler S, Holmstrom KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31.

    Article  PubMed  CAS  Google Scholar 

  80. Narendra D, Tanaka A, Suen DF, et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795–803.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Park J, Kim Y, Chung J. Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila. Dis Model Mech. 2009;2(7–8):336–40.

  82. Vives-Bauza C, Zhou C, Huang Y, et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA. 2010;107(1):378–83.

    Article  PubMed  Google Scholar 

  83. Thomas KJ, McCoy MK, Blackinton J, et al. DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet. 2010.

  84. Moussa CE. Parkin is dispensable for mitochondrial function, but its ubiquitin ligase activity is critical for macroautophagy and neurotransmitters: therapeutic potential beyond parkinson’s disease. Neurodegener Dis. 2015;15(5):259–70.

    Article  PubMed  CAS  Google Scholar 

  85. Kanki T, Wang K, Cao Y, et al. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell. 2009;17(1):98–109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Novak I, Kirkin V, McEwan DG, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010;11(1):45–51.

    Article  PubMed  CAS  Google Scholar 

  87. Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell. 2009;17(1):87–97.

    Article  PubMed  Google Scholar 

  88. Wild P, Dikic I. Mitochondria get a Parkin’ ticket. Nat Cell Biol. 2010;12(2):104–6.

    Article  PubMed  CAS  Google Scholar 

  89. Chen D, Gao F, Li B, et al. Parkin mono-ubiquitinates Bcl-2 and regulates autophagy. J Biol Chem. 2010;285(49):38214–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Sutovsky P, Moreno RD, Ramalho-Santos J, et al. Ubiquitin tag for sperm mitochondria. Nature. 1999;402(6760):371–2.

    Article  PubMed  CAS  Google Scholar 

  91. Rebeck GW, Hoe HS, Moussa CE. Beta-amyloid1-42 gene transfer model exhibits intraneuronal amyloid, gliosis, tau phosphorylation, and neuronal loss. J Biol Chem. 2010;285(10):7440–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6.

    Article  PubMed  CAS  Google Scholar 

  93. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26(20):3358–63.

    Article  PubMed  Google Scholar 

  94. Lonskaya I, Hebron ML, Desforges NM, et al. Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013;5(8):1247–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22(16):3315–28.

  96. Lonskaya I, Hebron ML, Algarzae NK, et al. Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease. Neuroscience. 2012;20(232C):90.

    Google Scholar 

  97. Lonskaya I, Hebron ML, Desforges NM, Schachter JB, Moussa CE. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med. 2014;92(4):373–86.

    Article  PubMed  CAS  Google Scholar 

  98. Kanazawa T, Taneike I, Akaishi R, et al. Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. J Biol Chem. 2004;279(9):8452–9.

    Article  PubMed  CAS  Google Scholar 

  99. Sarkar S, Krishna G, Imarisio S, et al. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet. 2008;17(2):170–8.

    Article  PubMed  CAS  Google Scholar 

  100. Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol. 2006;172(5):719–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Scarlatti F, Maffei R, Beau I, et al. Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 2008;15(8):1318–29.

    Article  PubMed  Google Scholar 

  102. Tobin JE, Latourelle JC, Lew MF, et al. Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study. Neurology. 2008;71(1):28–34.

    Article  PubMed  CAS  Google Scholar 

  103. van de Warrenburg BP, Lammens M, Lucking CB, et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology. 2001;56(4):555–7.

    Article  PubMed  Google Scholar 

  104. Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology. 1998;51(3):890–2.

    Article  PubMed  CAS  Google Scholar 

  105. Jellinger KA. Morphological substrates of mental dysfunction in Lewy body disease: an update. J Neural Transm Suppl. 2000;59:185–212.

    PubMed  CAS  Google Scholar 

  106. Dawson TM, Dawson VL. The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord. 2010;25(Suppl 1):S32–9.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41(12):1308–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41(12):1303–7.

    Article  PubMed  CAS  Google Scholar 

  109. Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994;369(6480):488–91.

    Article  PubMed  CAS  Google Scholar 

  110. Dawson HN, Ferreira A, Eyster MV, et al. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci. 2001;114(Pt 6):1179–87.

    PubMed  CAS  Google Scholar 

  111. Jimenez-Mateos EM, Gonzalez-Billault C, Dawson HN, et al. Role of MAP1B in axonal retrograde transport of mitochondria. Biochem J. 2006;397(1):53–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Walden H, Martinez-Torres RJ. Regulation of Parkin E3 ubiquitin ligase activity. Cell Mol Life Sci CMLS. 2012;69(18):3053–67.

    Article  PubMed  CAS  Google Scholar 

  113. Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16(6):495–501.

    Article  PubMed  CAS  Google Scholar 

  114. Kondapalli C, Kazlauskaite A, Zhang N, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2(5):120080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Trempe JF, Sauve V, Grenier K, et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science. 2013;340(6139):1451–5.

    Article  PubMed  CAS  Google Scholar 

  116. Wauer T, Komander D. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J. 2013;32(15):2099–112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205(2):143–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510(7503):162–6.

    Article  PubMed  CAS  Google Scholar 

  119. Kazlauskaite A, Kondapalli C, Gourlay R, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014;460(1):127–39.

    Article  PubMed  CAS  Google Scholar 

  120. Kazlauskaite A, Muqit MM. PINK1 and Parkin—mitochondrial interplay between phosphorylation and ubiquitylation in Parkinson’s disease. FEBS J. 2014.

  121. Caulfield TR, Fiesel FC, Moussaud-Lamodiere EL, et al. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase parkin. PLoS Comput Biol. 2014;10(11):e1003935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Hebron ML, Lonskaya I, Sharpe K, et al. Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6). J Biol Chem. 2013;288(6):4103–15.

    Article  PubMed  CAS  Google Scholar 

  123. Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014.

  124. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40.

    Article  PubMed  CAS  Google Scholar 

  125. Takeda A, Mallory M, Sundsmo M, et al. Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol. 1998;152(2):367–72.

    PubMed  PubMed Central  CAS  Google Scholar 

  126. Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science. 1996;274(5290):1197–9.

    Article  PubMed  CAS  Google Scholar 

  127. Miller DW, Hague SM, Clarimon J, et al. Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology. 2004;62(10):1835–8.

    Article  PubMed  CAS  Google Scholar 

  128. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet. 2004;364(9440):1167–9.

  129. Stefanis L. alpha-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2(2):a009399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Wong YC, Krainc D. alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1–13.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  131. Lashuel HA, Overk CR, Oueslati A, et al. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14(1):38–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Polymenidou M, Cleveland DW. Prion-like spread of protein aggregates in neurodegeneration. J Exp Med. 2012;209(5):889–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Games D, Valera E, Spencer B, et al. Reducing C-terminaltruncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci. 2014;34(28):9441–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211–8.

    Article  PubMed  CAS  Google Scholar 

  135. Rogers MB, Strobel G. Antibody against alpha-synuclein looks safe in phase 1. 2015. http://www.alzforum.org.

  136. Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Prothena Biosciences L. NCT02095171 single ascending dose study of PRX002 in healthy subjects. 2015.

  138. Prothena Biosciences L. NCT02157714 multiple ascending dose study of PRX002 in patients with Parkinson’s disease. 2014.

  139. Weihofen A, Patel H, Huy C, et al. Human-derived α-synuclein antibody BIIB054 binds pathologic forms of α-synuclein and attenuates transmission of α-synuclein in vitro and in vivo. Mov Disord. 2016;31(supplement 2).

  140. Biogen. NCT02459886 single-ascending dose study of BIIB054 in healthy participants and early Parkinson’s disease. 2015.

  141. AstraZeneca. NCT03272165 single ascending dose study of MEDI1341 in healthy volunteers. 2017.

  142. Georgetown U, Pagan F. NCT02281474 nilotinib in cognitively impaired Parkinson disease patients 001. 2014.

  143. Pagan F, Georgetown U. NCT02954978 impact of nilotinib on safety, tolerability, pharmacokinetics and biomarkers in Parkinson’s disease (PD Nilotinib). 2016.

  144. Hoffmann-La R, Prothena Biosciences L. NCT03100149 a study to evaluate the efficacy of RO7046015 in participants with early Parkinson’s disease (PASADENA). 2017.

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Funding

Georgetown University provided funding to Charbel E.-H. Moussa.

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  1. Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Room 203-C, Building D, 4000 Reservoir Rd. NW, Washington, DC, USA

    Alan J. Fowler & Charbel E.-H. Moussa

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  1. Alan J. Fowler
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Correspondence to Charbel E.-H. Moussa.

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Charbel E.-H. Moussa is listed as an inventor on a Georgetown University intellectual property patent to use tyrosine kinase inhibitors for the treatment of neurodegenerative diseases. Alan J. Fowler has no conflict of interest directly relevant to the content of this article.

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Fowler, A.J., Moussa, C.EH. Activating Autophagy as a Therapeutic Strategy for Parkinson’s Disease. CNS Drugs 32, 1–11 (2018). https://doi.org/10.1007/s40263-018-0497-5

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