Autophagy in age-associated neurodegeneration

Cells

Volumn 7, Issue 5, 2018, Pages

  Metaxakis, Athanasios ^a   Ploumi, Christina ^a,b   Tavernarakis, Nektarios ^a,b  

^a INSTITUTE OF MOLECULAR BIOLOGY AND BIOTECHNOLOGY   (Greece)

^b UNIVERSITY OF CRETE   (Greece)

Author keywords

Ageing; Alzheimer s disease; Amyotrophic lateral sclerosis; Autophagy; Huntington s disease; Mitophagy; Neurodegeneration; Parkinson s sisease; Protein aggregation; Treatment

Indexed keywords

ADAPTOR PROTEIN; ALPHA SYNUCLEIN; AUTOPHAGY RELATED PROTEIN 12; AUTOPHAGY RELATED PROTEIN 5; AUTOPHAGY RELATED PROTEIN 7; BECLIN 1; BRCA1 PROTEIN; CARBAMAZEPINE; CASPASE 3; COPPER ZINC SUPEROXIDE DISMUTASE; DEATH ASSOCIATED PROTEIN KINASE; DYNEIN ADENOSINE TRIPHOSPHATASE; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; OPTINEURIN; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLINOSITOL 3 KINASE; PRESENILIN 1; RAPAMYCIN; SERINE THREONINE PROTEIN KINASE ULK1; SIRTUIN 1; SNARE PROTEIN; TAU PROTEIN; TRANSCRIPTION FACTOR; VALOSIN CONTAINING PROTEIN;

AGING; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; BIOGENESIS; CELL SURVIVAL; DEGENERATIVE DISEASE; DOWN REGULATION; ELECTRON MICROSCOPY; GENE EXPRESSION; GENE OVEREXPRESSION; HOMEOSTASIS; HUMAN; HUNTINGTON CHOREA; LOSS OF FUNCTION MUTATION; MITOPHAGY; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; PI3K/AKT SIGNALING; PROTEIN AGGREGATION; PROTEIN TARGETING; PROTEINOSIS; REVIEW; TUMOR SUPPRESSOR GENE; UPREGULATION;

EID: 85053720932     PISSN: None     EISSN: 20734409     Source Type: Journal    
DOI: 10.3390/cells7050037     Document Type: Review

References (234)

1. Yorimitsu, T.; Klionsky, D.J. Autophagy: Molecular machinery for self-eating. Cell Death Differ. 2005, 12 (Suppl. 2), 1542–1552.
2. Tsukada, M.; Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of saccharomyces cerevisiae. FEBS Lett. 1993, 333, 169–174.
3. Harding, T.M.; Morano, K.A.; Scott, S.V.; Klionsky, D.J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 1995, 131, 591–602.
4. Guan, J.L.; Simon, A.K.; Prescott, M.; Menendez, J.A.; Liu, F.; Wang, F.; Wang, C.; Wolvetang, E.; Vazquez-Martin, A.; Zhang, J. Autophagy in stem cells. Autophagy 2013, 9, 830–849.
5. Mizushima, N.; Komatsu, M. Autophagy: Renovation of cells and tissues. Cell 2011, 147, 728–741.
6. Shen, H.M.; Mizushima, N. At the end of the autophagic road: An emerging understanding of lysosomal functions in autophagy. Trends Biochem. Sci. 2014, 39, 61–71.
7. Nikoletopoulou, V.; Sidiropoulou, K.; Kallergi, E.; Dalezios, Y.; Tavernarakis, N. Modulation of autophagy by bdnf underlies synaptic plasticity. Cell Metab. 2017, 26, 230–242.e5.
8. Rubinsztein, D.C.; Marino, G.; Kroemer, G. Autophagy and aging. Cell 2011, 146, 682–695.
9. Cuervo, A.M.; Macian, F. Autophagy and the immune function in aging. Curr. Opin. Immunol. 2014, 29, 97–104.
10. Galluzzi, L.; Kroemer, G. Amino acid deprivation promotes intestinal homeostasis through autophagy. Oncotarget 2016, 7, 29877–29878.
11. Wirawan, E.; Vanden Berghe, T.; Lippens, S.; Agostinis, P.; Vandenabeele, P. Autophagy: For better or for worse. Cell Res. 2012, 22, 43–61.
12. Lionaki, E.; Markaki, M.; Tavernarakis, N. Autophagy and ageing: Insights from invertebrate model organisms. Ageing Res. Rev. 2013, 12, 413–428.
13. Bjedov, I.; Partridge, L. A longer and healthier life with tor down-regulation: Genetics and drugs. Biochem. Soc. Trans. 2011, 39, 460–465.
14. Cuervo, A.M. Autophagy and aging: Keeping that old broom working. Trends Genet. 2008, 24, 604–612.
15. Koga, H.; Cuervo, A.M. Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration. Neurobiol. Dis. 2011, 43, 29–37.
16. Kiriyama, Y.; Nochi, H. The function of autophagy in neurodegenerative diseases. Int. J. Mol. Sci. 2015, 16, 26797–26812.
17. Nakamura, S.; Yoshimori, T. Autophagy and longevity. Mol. Cells 2018, 41, 65–72.
18. Niccoli, T.; Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 2012, 22, R74–R752.
19. Yang, L.; Wang, H.; Liu, L.; Xie, A. The role of insulin/igf-1/pi3k/akt/gsk3beta signaling in parkinson’s disease dementia. Front. Neurosci. 2018, 12, 73.
20. He, C.; Klionsky, D.J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 2009, 43, 67–93.
21. Sun, L.; Zhao, M.; Liu, M.; Su, P.; Zhang, J.; Li, Y.; Yang, X.; Wu, Z. Suppression of foxo3a attenuates neurobehavioral deficits after traumatic brain injury through inhibiting neuronal autophagy. Behav. Brain Res. 2018, 337, 271–279.
22. Chu, C.T. Autophagic stress in neuronal injury and disease. J. Neuropathol. Exp. Neurol. 2006, 65, 423–432.
23. Zhang, X.J.; Chen, S.; Huang, K.X.; Le, W.D. Why should autophagic flux be assessed? Acta Pharmacol. Sin. 2013, 34, 595–599.
24. Hara, T.; Nakamura, K.; Matsui, M.; Yamamoto, A.; Nakahara, Y.; Suzuki-Migishima, R.; Yokoyama, M.; Mishima, K.; Saito, I.; Okano, H. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441, 885–889.
25. Komatsu, M.; Waguri, S.; Chiba, T.; Murata, S.; Iwata, J.; Tanida, I.; Ueno, T.; Koike, M.; Uchiyama, Y.; Kominami, E. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006, 441, 880–884.
26. Lipinski, M.M.; Zheng, B.; Lu, T.; Yan, Z.; Py, B.F.; Ng, A.; Xavier, R.J.; Li, C.; Yankner, B.A.; Scherzer, C.R. et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2010, 107, 14164–14169.
27. Button, R.W.; Luo, S.; Rubinsztein, D.C. Autophagic activity in neuronal cell death. Neurosci. Bull. 2015, 31, 382–394.
28. Kroemer, G.; Levine, B. Autophagic cell death: The story of a misnomer. Nat. Rev. Mol. Cell Biol. 2008, 9, 1004–1010.
29. Lee, J.A.; Gao, F.B. Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional escrt-iii in frontotemporal dementia. J. Neurosci. 2009, 29, 8506–8511.
30. Kroemer, G.; Marino, G.; Levine, B. Autophagy and the integrated stress response. Mol. Cell 2010, 40, 280–293.
31. Napolitano, G.; Ballabio, A. Tfeb at a glance. J. Cell Sci. 2016, 129, 2475–2481.
32. Mizushima, N.; Yoshimori, T.; Ohsumi, Y. The role of atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 2011, 27, 107–132.
33. Karanasios, E.; Stapleton, E.; Manifava, M.; Kaizuka, T.; Mizushima, N.; Walker, S.A.; Ktistakis, N.T. Dynamic association of the ulk1 complex with omegasomes during autophagy induction. J. Cell Sci. 2013, 126, 5224–5238.
34. Ganley, I.G.; Lam du, H.; Wang, J.; Ding, X.; Chen, S.; Jiang, X. Ulk1.Atg13.Fip200 complex mediates mtor signaling and is essential for autophagy. J. Biol. Chem. 2009, 284, 12297–12305.
35. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. Ampk and mtor regulate autophagy through direct phosphorylation of ulk1. Nat. Cell Biol. 2011, 13, 132–141.
36. Russell, R.C.; Tian, Y.; Yuan, H.; Park, H.W.; Chang, Y.Y.; Kim, J.; Kim, H.; Neufeld, T.P.; Dillin, A.; Guan, K.L. Ulk1 induces autophagy by phosphorylating beclin-1 and activating vps34 lipid kinase. Nat. Cell Biol. 2013, 15, 741–750.
37. Zhang, D.; Wang, W.; Sun, X.; Xu, D.; Wang, C.; Zhang, Q.; Wang, H.; Luo, W.; Chen, Y.; Chen, H. et al. Ampk regulates autophagy by phosphorylating becn1 at threonine 388. Autophagy 2016, 12, 1447–1459.
38. Proikas-Cezanne, T.; Ruckerbauer, S.; Stierhof, Y.D.; Berg, C.; Nordheim, A. Human wipi-1 puncta-formation: A novel assay to assess mammalian autophagy. FEBS Lett. 2007, 581, 3396–3404.
39. Polson, H.E.; de Lartigue, J.; Rigden, D.J.; Reedijk, M.; Urbe, S.; Clague, M.J.; Tooze, S.A. Mammalian atg18 (wipi2) localizes to omegasome-anchored phagophores and positively regulates lc3 lipidation. Autophagy 2010, 6, 506–522.
40. Bakula, D.; Muller, A.J.; Zuleger, T.; Takacs, Z.; Franz-Wachtel, M.; Thost, A.K.; Brigger, D.; Tschan, M.P.; Frickey, T.; Robenek, H. et al. Wipi3 and wipi4 beta-propellers are scaffolds for lkb1-ampk-tsc signalling circuits in the control of autophagy. Nat. Commun. 2017, 8, 15637.
41. Romanov, J.; Walczak, M.; Ibiricu, I.; Schuchner, S.; Ogris, E.; Kraft, C.; Martens, S. Mechanism and functions of membrane binding by the atg5-atg12/atg16 complex during autophagosome formation. EMBO J. 2012, 31, 4304–4317.
42. Ichimura, Y.; Kirisako, T.; Takao, T.; Satomi, Y.; Shimonishi, Y.; Ishihara, N.; Mizushima, N.; Tanida, I.; Kominami, E.; Ohsumi, M. et al. A ubiquitin-like system mediates protein lipidation. Nature 2000, 408, 488–492.
43. Yamamoto, H.; Kakuta, S.; Watanabe, T.M.; Kitamura, A.; Sekito, T.; Kondo-Kakuta, C.; Ichikawa, R.; Kinjo, M.; Ohsumi, Y. Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J. Cell Biol. 2012, 198, 219–233.
44. Zhou, C.; Ma, K.; Gao, R.; Mu, C.; Chen, L.; Liu, Q.; Luo, Q.; Feng, D.; Zhu, Y.; Chen, Q. Regulation of matg9 trafficking by src- and ulk1-mediated phosphorylation in basal and starvation-induced autophagy. Cell Res. 2017, 27, 184–201.
45. Zaffagnini, G.; Martens, S. Mechanisms of selective autophagy. J. Mol. Biol. 2016, 428, 1714–1724.
46. Deng, Z.; Purtell, K.; Lachance, V.; Wold, M.S.; Chen, S.; Yue, Z. Autophagy receptors and neurodegenerative diseases. Trends Cell Biol. 2017, 27, 491–504.
47. Knorr, R.L.; Lipowsky, R.; Dimova, R. Autophagosome closure requires membrane scission. Autophagy 2015, 11, 2134–2137.
48. Velikkakath, A.K.; Nishimura, T.; Oita, E.; Ishihara, N.; Mizushima, N. Mammalian atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol. Biol. Cell 2012, 23, 896–909.
49. Mackeh, R.; Perdiz, D.; Lorin, S.; Codogno, P.; Pous, C. Autophagy and microtubules—New story, old players. J. Cell Sci. 2013, 126, 1071–1080.
50. Wang, Y.; Li, L.; Hou, C.; Lai, Y.; Long, J.; Liu, J.; Zhong, Q.; Diao, J. Snare-mediated membrane fusion in autophagy. Semin. Cell Dev. Biol. 2016, 60, 97–104.
51. Jiang, P.; Nishimura, T.; Sakamaki, Y.; Itakura, E.; Hatta, T.; Natsume, T.; Mizushima, N. The hops complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol. Biol. Cell 2014, 25, 1327–1337.
52. Berg, T.O.; Fengsrud, M.; Stromhaug, P.E.; Berg, T.; Seglen, P.O. Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem. 1998, 273, 21883–21892.
53. Sanchez-Wandelmer, J.; Reggiori, F. Amphisomes: Out of the autophagosome shadow? EMBO J. 2013, 32, 3116–3118.
54. Yu, Z.Q.; Ni, T.; Hong, B.; Wang, H.Y.; Jiang, F.J.; Zou, S.; Chen, Y.; Zheng, X.L.; Klionsky, D.J.; Liang, Y. et al. Dual roles of atg8-pe deconjugation by atg4 in autophagy. Autophagy 2012, 8, 883–892.
55. Mauvezin, C.; Nagy, P.; Juhasz, G.; Neufeld, T.P. Autophagosome-lysosome fusion is independent of v-atpase-mediated acidification. Nat. Commun. 2015, 6, 7007.
56. Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C.P. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement. J. Alzheimers Assoc. 2013, 9, 63–75.e62.
57. Nixon, R.A.; Wegiel, J.; Kumar, A.; Yu, W.H.; Peterhoff, C.; Cataldo, A.; Cuervo, A.M. Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 2005, 64, 113–122.
58. Yu, W.H.; Cuervo, A.M.; Kumar, A.; Peterhoff, C.M.; Schmidt, S.D.; Lee, J.H.; Mohan, P.S.; Mercken, M.; Farmery, M.R.; Tjernberg, L.O. et al. Macroautophagy--a novel beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 2005, 171, 87–98.
59. Anglade, P.; Vyas, S.; Javoy-Agid, F.; Herrero, M.T.; Michel, P.P.; Marquez, J.; Mouatt-Prigent, A.; Ruberg, M.; Hirsch, E.C.; Agid, Y. Apoptosis and autophagy in nigral neurons of patients with parkinson’s disease. Histol. Histopathol. 1997, 12, 25–31.
60. Boland, B.; Kumar, A.; Lee, S.; Platt, F.M.; Wegiel, J.; Yu, W.H.; Nixon, R.A. Autophagy induction and autophagosome clearance in neurons: Relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 2008, 28, 6926–6937.
61. Webb, J.L.; Ravikumar, B.; Rubinsztein, D.C. Microtubule disruption inhibits autophagosome-lysosome fusion: Implications for studying the roles of aggresomes in polyglutamine diseases. Int. J. Biochem. Cell Biol. 2004, 36, 2541–2550.
62. Nixon, R.A. Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiol. Aging 2005, 26, 373–382.
63. Wang, J.; Gu, B.J.; Masters, C.L.; Wang, Y.J. A systemic view of Alzheimer disease—Insights from amyloid-beta metabolism beyond the brain. Nat. Rev. Neurol. 2017, 13, 703.
64. Chen, G.F.; Xu, T.H.; Yan, Y.; Zhou, Y.R.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017, 38, 1205–1235.
65. Yankner, B.A.; Lu, T. Amyloid beta-protein toxicity and the pathogenesis of Alzheimer disease. J. Biol. Chem. 2009, 284, 4755–4759.
66. Bloom, G.S. Amyloid-beta and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014, 71, 505–508.
67. Vassar, R.; Kovacs, D.M.; Yan, R.; Wong, P.C. The beta-secretase enzyme bace in health and Alzheimer’s disease: Regulation, cell biology, function, and therapeutic potential. J. Neurosci. 2009, 29, 12787–12794.
68. Velliquette, R.A.; O’Connor, T.; Vassar, R. Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in app transgenic mice: Possible early events in Alzheimer’s disease pathogenesis. J. Neurosci. 2005, 25, 10874–10883.
69. Alonso, A.C.; Li, B.; Grundke-Iqbal, I.; Iqbal, K. Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 2008, 5, 375–384.
70. Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 2010, 7, 656–664.
71. Li, B.; Chohan, M.O.; Grundke-Iqbal, I.; Iqbal, K. Disruption of microtubule network by alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol. 2007, 113, 501–511.
72. Wolfe, D.M.; Lee, J.H.; Kumar, A.; Lee, S.; Orenstein, S.J.; Nixon, R.A. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 2013, 37, 1949–1961.
73. Nilsson, P.; Loganathan, K.; Sekiguchi, M.; Matsuba, Y.; Hui, K.; Tsubuki, S.; Tanaka, M.; Iwata, N.; Saito, T.; Saido, T.C. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 2013, 5, 61–69.
74. Nilsson, P.; Sekiguchi, M.; Akagi, T.; Izumi, S.; Komori, T.; Hui, K.; Sorgjerd, K.; Tanaka, M.; Saito, T.; Iwata, N. et al. Autophagy-related protein 7 deficiency in amyloid beta (abeta) precursor protein transgenic mice decreases abeta in the multivesicular bodies and induces abeta accumulation in the golgi. Am. J. Pathol. 2015, 185, 305–313.
75. Tammineni, P.; Ye, X.; Feng, T.; Aikal, D.; Cai, Q. Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons. eLife 2017, 6, e21776.
76. Majid, T.; Ali, Y.O.; Venkitaramani, D.V.; Jang, M.K.; Lu, H.C.; Pautler, R.G. In vivo axonal transport deficits in a mouse model of fronto-temporal dementia. NeuroImage Clin. 2014, 4, 711–717.
77. Lee, J.H.; Yu, W.H.; Kumar, A.; Lee, S.; Mohan, P.S.; Peterhoff, C.M.; Wolfe, D.M.; Martinez-Vicente, M.; Massey, A.C.; Sovak, G. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by alzheimer-related ps1 mutations. Cell 2010, 141, 1146–1158.
78. Kelleher, R.J., 3rd; Shen, J. Presenilin-1 mutations and Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2017, 114, 629–631.
79. Veugelen, S.; Saito, T.; Saido, T.C.; Chavez-Gutierrez, L.; De Strooper, B. Familial Alzheimer’s disease mutations in presenilin generate amyloidogenic abeta peptide seeds. Neuron 2016, 90, 410–416.
80. Xia, D.; Watanabe, H.; Wu, B.; Lee, S.H.; Li, Y.; Tsvetkov, E.; Bolshakov, V.Y.; Shen, J.; Kelleher, R.J., 3rd. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer’s disease. Neuron 2015, 85, 967–981.
81. Xia, D.; Kelleher, R.J., 3rd; Shen, J. Loss of abeta43 production caused by presenilin-1 mutations in the knockin mouse brain. Neuron 2016, 90, 417–422.
82. Ling, D.; Song, H.J.; Garza, D.; Neufeld, T.P.; Salvaterra, P.M. Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in drosophila. PLoS ONE 2009, 4, e4201.
83. Lucin, K.M.; O’Brien, C.E.; Bieri, G.; Czirr, E.; Mosher, K.I.; Abbey, R.J.; Mastroeni, D.F.; Rogers, J.; Spencer, B.; Masliah, E. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 2013, 79, 873–886.
84. Pickford, F.; Masliah, E.; Britschgi, M.; Lucin, K.; Narasimhan, R.; Jaeger, P.A.; Small, S.; Spencer, B.; Rockenstein, E.; Levine, B. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Investig. 2008, 118, 2190–2199.
85. Jaeger, P.A.; Pickford, F.; Sun, C.H.; Lucin, K.M.; Masliah, E.; Wyss-Coray, T. Regulation of amyloid precursor protein processing by the beclin 1 complex. PLoS ONE 2010, 5, e11102.
86. Rohn, T.T.; Wirawan, E.; Brown, R.J.; Harris, J.R.; Masliah, E.; Vandenabeele, P. Depletion of beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiol. Dis. 2011, 43, 68–78.
87. Rocchi, A.; Yamamoto, S.; Ting, T.; Fan, Y.; Sadleir, K.; Wang, Y.; Zhang, W.; Huang, S.; Levine, B.; Vassar, R. et al. A becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer’s disease. PLoS Genet. 2017, 13, e1006962.
88. Omata, Y.; Lim, Y.M.; Akao, Y.; Tsuda, L. Age-induced reduction of autophagy-related gene expression is associated with onset of Alzheimer’s disease. Am. J. Neurodegener. Dis. 2014, 3, 134–142.
89. Yang, C.; Cai, C.Z.; Song, J.X.; Tan, J.Q.; Durairajan, S.S.K.; Iyaswamy, A.; Wu, M.Y.; Chen, L.L.; Yue, Z.; Li, M. et al. Nrbf2 is involved in the autophagic degradation process of app-ctfs in Alzheimer disease models. Autophagy 2017, 13, 2028–2040.
90. Caccamo, A.; Majumder, S.; Richardson, A.; Strong, R.; Oddo, S. Molecular interplay between mammalian target of rapamycin (mtor), amyloid-beta, and tau: Effects on cognitive impairments. J. Biol. Chem. 2010, 285, 13107–13120.
91. Caccamo, A.; Magri, A.; Medina, D.X.; Wisely, E.V.; Lopez-Aranda, M.F.; Silva, A.J.; Oddo, S. Mtor regulates tau phosphorylation and degradation: Implications for Alzheimer’s disease and other tauopathies. Aging Cell 2013, 12, 370–380.
92. Tang, Z.; Ioja, E.; Bereczki, E.; Hultenby, K.; Li, C.; Guan, Z.; Winblad, B.; Pei, J.J. Mtor mediates tau localization and secretion: Implication for Alzheimer’s disease. Biochim. Biophys. Acta 2015, 1853, 1646–1657.
93. Elbaz, A.; Carcaillon, L.; Kab, S.; Moisan, F. Epidemiology of parkinson’s disease. Rev. Neurol. 2016, 172, 14–26.
94. Jankovic, J. Parkinson’s disease: Clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 2008, 79, 368–376.
95. Brichta, L.; Greengard, P.; Flajolet, M. Advances in the pharmacological treatment of parkinson’s disease: Targeting neurotransmitter systems. Trends Neurosci. 2013, 36, 543–554.
96. Kalia, L.V.; Lang, A.E. Parkinson’s disease. Lancet 2015, 386, 896–912.
97. De Vos, K.J.; Grierson, A.J.; Ackerley, S.; Miller, C.C. Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 2008, 31, 151–173.
98. Trimmer, P.A.; Bennett, J.P., Jr. The cybrid model of sporadic parkinson’s disease. Exp. Neurol. 2009, 218, 320–325.
99. Abeliovich, A.; Gitler, A.D. Defects in trafficking bridge parkinson’s disease pathology and genetics. Nature 2016, 539, 207–216.
100. Dehay, B.; Bove, J.; Rodriguez-Muela, N.; Perier, C.; Recasens, A.; Boya, P.; Vila, M. Pathogenic lysosomal depletion in parkinson’s disease. J. Neurosci. 2010, 30, 12535–12544.
101. Chu, Y.; Dodiya, H.; Aebischer, P.; Olanow, C.W.; Kordower, J.H. Alterations in lysosomal and proteasomal markers in parkinson’s disease: Relationship to alpha-synuclein inclusions. Neurobiol. Dis. 2009, 35, 385–398.
102. Settembre, C.; Di Malta, C.; Polito, V.A.; Garcia Arencibia, M.; Vetrini, F.; Erdin, S.; Erdin, S.U.; Huynh, T.; Medina, D.; Colella, P. et al. Tfeb links autophagy to lysosomal biogenesis. Science 2011, 332, 1429–1433.
103. Whitworth, A.J.; Pallanck, L.J. Pink1/parkin mitophagy and neurodegeneration-what do we really know in vivo? Curr. Opin. Genet. Dev. 2017, 44, 47–53.
104. Valente, E.M.; Abou-Sleiman, P.M.; Caputo, V.; Muqit, M.M.; Harvey, K.; Gispert, S.; Ali, Z.; Del Turco, D.; Bentivoglio, A.R.; Healy, D.G. et al. Hereditary early-onset parkinson’s disease caused by mutations in pink1. Science 2004, 304, 1158–1160.
105. Valente, E.M.; Brancati, F.; Caputo, V.; Graham, E.A.; Davis, M.B.; Ferraris, A.; Breteler, M.M.; Gasser, T.; Bonifati, V.; Bentivoglio, A.R. et al. Park6 is a common cause of familial parkinsonism. Neurol. Sci. 2002, 23 (Suppl. 2), S117–S118.
106. Hardy, J. Genetic analysis of pathways to parkinson disease. Neuron 2010, 68, 201–206.
107. Jin, S.M.; Lazarou, M.; Wang, C.; Kane, L.A.; Narendra, D.P.; Youle, R.J. Mitochondrial membrane potential regulates pink1 import and proteolytic destabilization by parl. J. Cell Biol. 2010, 191, 933–942.
108. Meissner, C.; Lorenz, H.; Weihofen, A.; Selkoe, D.J.; Lemberg, M.K. The mitochondrial intramembrane protease parl cleaves human pink1 to regulate pink1 trafficking. J. Neurochem. 2011, 117, 856–867.
109. Yamano, K.; Youle, R.J. Pink1 is degraded through the n-end rule pathway. Autophagy 2013, 9, 1758–1769.
110. Okatsu, K.; Oka, T.; Iguchi, M.; Imamura, K.; Kosako, H.; Tani, N.; Kimura, M.; Go, E.; Koyano, F.; Funayama, M. et al. Pink1 autophosphorylation upon membrane potential dissipation is essential for parkin recruitment to damaged mitochondria. Nat. Commun. 2012, 3, 1016.
111. Kazlauskaite, A.; Kondapalli, C.; Gourlay, R.; Campbell, D.G.; Ritorto, M.S.; Hofmann, K.; Alessi, D.R.; Knebel, A.; Trost, M.; Muqit, M.M. Parkin is activated by pink1-dependent phosphorylation of ubiquitin at ser65. Biochem. J. 2014, 460, 127–139.
112. Koyano, F.; Okatsu, K.; Kosako, H.; Tamura, Y.; Go, E.; Kimura, M.; Kimura, Y.; Tsuchiya, H.; Yoshihara, H.; Hirokawa, T. et al. Ubiquitin is phosphorylated by pink1 to activate parkin. Nature 2014, 510, 162–166.
113. Wauer, T.; Simicek, M.; Schubert, A.; Komander, D. Mechanism of phospho-ubiquitin-induced parkin activation. Nature 2015, 524, 370–374.
114. Knuppertz, L.; Osiewacz, H.D. Orchestrating the network of molecular pathways affecting aging: Role of nonselective autophagy and mitophagy. Mech. Ageing Dev. 2016, 153, 30–40.
115. Ross, C.A.; Tabrizi, S.J. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol. 2011, 10, 83–98.
116. Dayalu, P.; Albin, R.L. Huntington disease: Pathogenesis and treatment. Neurol. Clin. 2015, 33, 101–114.
117. The huntington’s disease collaborative research group. A novel gene containing a trinucleotide repeat that is expanded and unstable on huntington’s disease chromosomes. Cell 1993, 72, 971–983.
118. Saudou, F.; Humbert, S. The biology of huntingtin. Neuron 2016, 89, 910–926.
119. Schwab, L.C.; Richetin, K.; Barker, R.A.; Deglon, N. Formation of hippocampal mhtt aggregates leads to impaired spatial memory, hippocampal activation and adult neurogenesis. Neurobiol. Dis. 2017, 102, 105–112.
120. Harjes, P.; Wanker, E.E. The hunt for huntingtin function: Interaction partners tell many different stories. Trends Biochem. Sci. 2003, 28, 425–433.
121. Ochaba, J.; Lukacsovich, T.; Csikos, G.; Zheng, S.; Margulis, J.; Salazar, L.; Mao, K.; Lau, A.L.; Yeung, S.Y.; Humbert, S. et al. Potential function for the huntingtin protein as a scaffold for selective autophagy. Proc. Natl. Acad. Sci. USA 2014, 111, 16889–16894.
122. Steffan, J.S. Does huntingtin play a role in selective macroautophagy? Cell Cycle 2010, 9, 3401–3413.
123. Dragatsis, I.; Levine, M.S.; Zeitlin, S. Inactivation of hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 2000, 26, 300–306.
124. Nasir, J.; Floresco, S.B.; O’Kusky, J.R.; Diewert, V.M.; Richman, J.M.; Zeisler, J.; Borowski, A.; Marth, J.D.; Phillips, A.G.; Hayden, M.R. Targeted disruption of the huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995, 81, 811–823.
125. Rui, Y.N.; Xu, Z.; Patel, B.; Chen, Z.; Chen, D.; Tito, A.; David, G.; Sun, Y.; Stimming, E.F.; Bellen, H.J. et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 2015, 17, 262–275.
126. Zheng, S.; Clabough, E.B.; Sarkar, S.; Futter, M.; Rubinsztein, D.C.; Zeitlin, S.O. Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet. 2010, 6, e1000838.
127. Martinez, J.E.; Vershinin, M.D.; Shubeita, G.T.; Gross, S.P. On the use of in vivo cargo velocity as a biophysical marker. Biochem. Biophys. Res. Commun. 2007, 353, 835–840.
128. Ravikumar, B.; Vacher, C.; Berger, Z.; Davies, J.E.; Luo, S.; Oroz, L.G.; Scaravilli, F.; Easton, D.F.; Duden, R.; O’Kane, C.J. 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, 585–595.
129. Rose, C.; Menzies, F.M.; Renna, M.; Acevedo-Arozena, A.; Corrochano, S.; Sadiq, O.; Brown, S.D.; Rubinsztein, D.C. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of huntington’s disease. Hum. Mol. Genet. 2010, 19, 2144–2153.
130. Tanaka, M.; Machida, Y.; Niu, S.; Ikeda, T.; Jana, N.R.; Doi, H.; Kurosawa, M.; Nekooki, M.; Nukina, N. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of huntington disease. Nat. Med. 2004, 10, 148–154.
131. Tsunemi, T.; Ashe, T.D.; Morrison, B.E.; Soriano, K.R.; Au, J.; Roque, R.A.; Lazarowski, E.R.; Damian, V.A.; Masliah, E.; La Spada, A.R. Pgc-1alpha rescues huntington’s disease proteotoxicity by preventing oxidative stress and promoting tfeb function. Sci. Transl. Med. 2012, 4, 142ra197.
132. Logroscino, G.; Traynor, B.J.; Hardiman, O.; Chio, A.; Mitchell, D.; Swingler, R.J.; Millul, A.; Benn, E.; Beghi, E. Incidence of amyotrophic lateral sclerosis in europe. J. Neurol. Neurosurg. Psychiatry 2010, 81, 385–390.
133. Niccoli, T.; Partridge, L.; Isaacs, A.M. Ageing as a risk factor for als/ftd. Hum. Mol. Genet. 2017, 26, R105–R113.
134. Ajroud-Driss, S.; Siddique, T. Sporadic and hereditary amyotrophic lateral sclerosis (als). Biochim. Biophys. Acta 2015, 1852, 679–684.
135. Wang, Q.; Johnson, J.L.; Agar, N.Y.; Agar, J.N. Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol. 2008, 6, e170.
136. Blokhuis, A.M.; Groen, E.J.; Koppers, M.; van den Berg, L.H.; Pasterkamp, R.J. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013, 125, 777–794.
137. Tian, F.; Morimoto, N.; Liu, W.; Ohta, Y.; Deguchi, K.; Miyazaki, K.; Abe, K. In vivo optical imaging of motor neuron autophagy in a mouse model of amyotrophic lateral sclerosis. Autophagy 2011, 7, 985–992.
138. Sasaki, S. Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 2011, 70, 349–359.
139. Chen, S.; Zhang, X.; Song, L.; Le, W. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 2012, 22, 110–116.
140. Deng, Z.; Sheehan, P.; Chen, S.; Yue, Z. Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease? Mol. Neurodegener. 2017, 12, 90.
141. Chen, Y.; Liu, H.; Guan, Y.; Wang, Q.; Zhou, F.; Jie, L.; Ju, J.; Pu, L.; Du, H.; Wang, X. The altered autophagy mediated by tfeb in animal and cell models of amyotrophic lateral sclerosis. Am. J. Transl. Res. 2015, 7, 1574–1587.
142. Nassif, M.; Valenzuela, V.; Rojas-Rivera, D.; Vidal, R.; Matus, S.; Castillo, K.; Fuentealba, Y.; Kroemer, G.; Levine, B.; Hetz, C. Pathogenic role of becn1/beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 2014, 10, 1256–1271.
143. Bose, J.K.; Huang, C.C.; Shen, C.K. Regulation of autophagy by neuropathological protein tdp-43. J. Biol. Chem. 2011, 286, 44441–44448.
144. Xia, Q.; Wang, H.; Hao, Z.; Fu, C.; Hu, Q.; Gao, F.; Ren, H.; Chen, D.; Han, J.; Ying, Z. et al. Tdp-43 loss of function increases tfeb activity and blocks autophagosome-lysosome fusion. EMBO J. 2016, 35, 121–142.
145. Mori, K.; Weng, S.M.; Arzberger, T.; May, S.; Rentzsch, K.; Kremmer, E.; Schmid, B.; Kretzschmar, H.A.; Cruts, M.; Van Broeckhoven, C. et al. The c9orf72 ggggcc repeat is translated into aggregating dipeptide-repeat proteins in ftld/als. Science 2013, 339, 1335–1338.
146. Farg, M.A.; Sundaramoorthy, V.; Sultana, J.M.; Yang, S.; Atkinson, R.A.K.; Levina, V.; Halloran, M.A.; Gleeson, P.A.; Blair, I.P.; Soo, K.Y. et al. C9orf72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum. Mol. Genet. 2017, 26, 4093–4094.
147. Corbier, C.; Sellier, C. C9orf72 is a gdp/gtp exchange factor for rab8 and rab39 and regulates autophagy. Small GTPases 2017, 8, 181–186.
148. Webster, C.P.; Smith, E.F.; Bauer, C.S.; Moller, A.; Hautbergue, G.M.; Ferraiuolo, L.; Myszczynska, M.A.; Higginbottom, A.; Walsh, M.J.; Whitworth, A.J. et al. The c9orf72 protein interacts with rab1a and the ulk1 complex to regulate initiation of autophagy. EMBO J. 2016, 35, 1656–1676.
149. Webster, C.P.; Smith, E.F.; Grierson, A.J.; De Vos, K.J. C9orf72 plays a central role in rab gtpase-dependent regulation of autophagy. Small GTPases 2016, 1–10.
150. Fecto, F.; Yan, J.; Vemula, S.P.; Liu, E.; Yang, Y.; Chen, W.; Zheng, J.G.; Shi, Y.; Siddique, N.; Arrat, H. et al. Sqstm1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 2011, 68, 1440–1446.
151. Maruyama, H.; Morino, H.; Ito, H.; Izumi, Y.; Kato, H.; Watanabe, Y.; Kinoshita, Y.; Kamada, M.; Nodera, H.; Suzuki, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010, 465, 223–226.
152. Gal, J.; Strom, A.L.; Kwinter, D.M.; Kilty, R.; Zhang, J.; Shi, P.; Fu, W.; Wooten, M.W.; Zhu, H. Sequestosome 1/p62 links familial als mutant sod1 to lc3 via an ubiquitin-independent mechanism. J. Neurochem. 2009, 111, 1062–1073.
153. Brady, O.A.; Meng, P.; Zheng, Y.; Mao, Y.; Hu, F. Regulation of tdp-43 aggregation by phosphorylation and p62/sqstm1. J. Neurochem. 2011, 116, 248–259.
154. Goode, A.; Butler, K.; Long, J.; Cavey, J.; Scott, D.; Shaw, B.; Sollenberger, J.; Gell, C.; Johansen, T.; Oldham, N.J. et al. Defective recognition of lc3b by mutant sqstm1/p62 implicates impairment of autophagy as a pathogenic mechanism in als-ftld. Autophagy 2016, 12, 1094–1104.
155. Lattante, S.; de Calbiac, H.; Le Ber, I.; Brice, A.; Ciura, S.; Kabashi, E. Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of als/ftld. Hum. Mol. Genet. 2015, 24, 1682–1690.
156. Shen, W.C.; Li, H.Y.; Chen, G.C.; Chern, Y.; Tu, P.H. Mutations in the ubiquitin-binding domain of optn/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism. Autophagy 2015, 11, 685–700.
157. Wong, Y.C.; Holzbaur, E.L. Temporal dynamics of park2/parkin and optn/optineurin recruitment during the mitophagy of damaged mitochondria. Autophagy 2015, 11, 422–424.
158. Moore, A.S.; Holzbaur, E.L. Dynamic recruitment and activation of als-associated tbk1 with its target optineurin are required for efficient mitophagy. Proc. Natl. Acad. Sci. USA 2016, 113, E3349–E3358.
159. Wong, Y.C.; Holzbaur, E.L. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an als-linked mutation. Proc. Natl. Acad. Sci. USA 2014, 111, E4439–E4448.
160. Johnson, J.O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin, V.M.; Trojanowski, J.Q.; Gibbs, J.R.; Brunetti, M.; Gronka, S.; Wuu, J. et al. Exome sequencing reveals vcp mutations as a cause of familial als. Neuron 2010, 68, 857–864.
161. Tresse, E.; Salomons, F.A.; Vesa, J.; Bott, L.C.; Kimonis, V.; Yao, T.P.; Dantuma, N.P.; Taylor, J.P. Vcp/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause ibmpfd. Autophagy 2010, 6, 217–227.
162. Hafezparast, M.; Klocke, R.; Ruhrberg, C.; Marquardt, A.; Ahmad-Annuar, A.; Bowen, S.; Lalli, G.; Witherden, A.S.; Hummerich, H.; Nicholson, S. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003, 300, 808–812.
163. Ilieva, H.S.; Yamanaka, K.; Malkmus, S.; Kakinohana, O.; Yaksh, T.; Marsala, M.; Cleveland, D.W. Mutant dynein (loa) triggers proprioceptive axon loss that extends survival only in the sod1 als model with highest motor neuron death. Proc. Natl. Acad. Sci. USA 2008, 105, 12599–12604.
164. Puls, I.; Jonnakuty, C.; LaMonte, B.H.; Holzbaur, E.L.; Tokito, M.; Mann, E.; Floeter, M.K.; Bidus, K.; Drayna, D.; Oh, S.J. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 2003, 33, 455–456.
165. LaMonte, B.H.; Wallace, K.E.; Holloway, B.A.; Shelly, S.S.; Ascano, J.; Tokito, M.; Van Winkle, T.; Howland, D.S.; Holzbaur, E.L. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 2002, 34, 715–727.
166. Vilmont, V.; Cadot, B.; Vezin, E.; Le Grand, F.; Gomes, E.R. Dynein disruption perturbs post-synaptic components and contributes to impaired musk clustering at the nmj: Implication in als. Sci. Rep. 2016, 6, 27804.
167. Zhang, F.; Strom, A.L.; Fukada, K.; Lee, S.; Hayward, L.J.; Zhu, H. Interaction between familial amyotrophic lateral sclerosis (als)-linked sod1 mutants and the dynein complex. J. Biol. Chem. 2007, 282, 16691–16699.
168. Gamerdinger, M.; Kaya, A.M.; Wolfrum, U.; Clement, A.M.; Behl, C. Bag3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep. 2011, 12, 149–156.
169. Crippa, V.; Sau, D.; Rusmini, P.; Boncoraglio, A.; Onesto, E.; Bolzoni, E.; Galbiati, M.; Fontana, E.; Marino, M.; Carra, S. et al. The small heat shock protein b8 (hspb8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (als). Hum. Mol. Genet. 2010, 19, 3440–3456.
170. Crippa, V.; Boncoraglio, A.; Galbiati, M.; Aggarwal, T.; Rusmini, P.; Giorgetti, E.; Cristofani, R.; Carra, S.; Pennuto, M.; Poletti, A. Differential autophagy power in the spinal cord and muscle of transgenic als mice. Front. Cell. Neurosci. 2013, 7, 234.
171. Gamerdinger, M.; Hajieva, P.; Kaya, A.M.; Wolfrum, U.; Hartl, F.U.; Behl, C. Protein quality control during aging involves recruitment of the macroautophagy pathway by bag3. EMBO J. 2009, 28, 889–901.
172. Carra, S.; Seguin, S.J.; Lambert, H.; Landry, J. Hspb8 chaperone activity toward poly(q)-containing proteins depends on its association with bag3, a stimulator of macroautophagy. J. Biol. Chem. 2008, 283, 1437–1444.
173. Sturner, E.; Behl, C. The role of the multifunctional bag3 protein in cellular protein quality control and in disease. Front. Mol. Neurosci. 2017, 10, 177.
174. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795.
175. Rubinsztein, D.C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006, 443, 780–786.
176. Lopez-Otin, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217.
177. Ott, C.; Konig, J.; Hohn, A.; Jung, T.; Grune, T. Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts. Redox Biol. 2016, 10, 266–273.
178. Yang, F.; Chu, X.; Yin, M.; Liu, X.; Yuan, H.; Niu, Y.; Fu, L. Mtor and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits. Behav. Brain Res. 2014, 264, 82–90.
179. Diot, A.; Hinks-Roberts, A.; Lodge, T.; Liao, C.; Dombi, E.; Morten, K.; Brady, S.; Fratter, C.; Carver, J.; Muir, R. et al. A novel quantitative assay of mitophagy: Combining high content fluorescence microscopy and mitochondrial DNA load to quantify mitophagy and identify novel pharmacological tools against pathogenic heteroplasmic mtdna. Pharmacol. Res. 2015, 100, 24–35.
180. Diot, A.; Morten, K.; Poulton, J. Mitophagy plays a central role in mitochondrial ageing. Mamm. Genome 2016, 27, 381–395.
181. Lopez-Lluch, G.; Irusta, P.M.; Navas, P.; de Cabo, R. Mitochondrial biogenesis and healthy aging. Exp. Gerontol. 2008, 43, 813–819.
182. Onyango, I.G.; Lu, J.; Rodova, M.; Lezi, E.; Crafter, A.B.; Swerdlow, R.H. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim. Biophys. Acta 2010, 1802, 228–234.
183. Wenz, T. Mitochondria and pgc-1alpha in aging and age-associated diseases. J. Aging Res. 2011, 2011, 810619.
184. Picca, A.; Fracasso, F.; Pesce, V.; Cantatore, P.; Joseph, A.M.; Leeuwenburgh, C.; Gadaleta, M.N.; Lezza, A.M. Age- and calorie restriction-related changes in rat brain mitochondrial DNA and tfam binding. Age 2013, 35, 1607–1620.
185. Grimm, A.; Eckert, A. Brain aging and neurodegeneration: From a mitochondrial point of view. J. Neurochem. 2017, 143, 418–431.
186. Pyo, J.O.; Yoo, S.M.; Ahn, H.H.; Nah, J.; Hong, S.H.; Kam, T.I.; Jung, S.; Jung, Y.K. Overexpression of atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 2013, 4, 2300.
187. Matecic, M.; Smith, D.L.; Pan, X.; Maqani, N.; Bekiranov, S.; Boeke, J.D.; Smith, J.S. A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet. 2010, 6, e1000921.
188. Palikaras, K.; Lionaki, E.; Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in c. Elegans. Nature 2015, 521, 525–528.
189. Lee, J.H.; Budanov, A.V.; Park, E.J.; Birse, R.; Kim, T.E.; Perkins, G.A.; Ocorr, K.; Ellisman, M.H.; Bodmer, R.; Bier, E. et al. Sestrin as a feedback inhibitor of tor that prevents age-related pathologies. Science 2010, 327, 1223–1228.
190. Bjedov, I.; Toivonen, J.M.; Kerr, F.; Slack, C.; Jacobson, J.; Foley, A.; Partridge, L. Mechanisms of life span extension by rapamycin in the fruit fly drosophila melanogaster. Cell Metabol. 2010, 11, 35–46.
191. Hartleben, B.; Godel, M.; Meyer-Schwesinger, C.; Liu, S.; Ulrich, T.; Kobler, S.; Wiech, T.; Grahammer, F.; Arnold, S.J.; Lindenmeyer, M.T. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Investig. 2010, 120, 1084–1096.
192. Rana, A.; Rera, M.; Walker, D.W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc. Natl. Acad. Sci. USA 2013, 110, 8638–8643.
193. Wood, J.G.; Rogina, B.; Lavu, S.; Howitz, K.; Helfand, S.L.; Tatar, M.; Sinclair, D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004, 430, 686–689.
194. Morselli, E.; Marino, G.; Bennetzen, M.V.; Eisenberg, T.; Megalou, E.; Schroeder, S.; Cabrera, S.; Benit, P.; Rustin, P.; Criollo, A. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 2011, 192, 615–629.
195. Choi, M.S.; Kim, Y.; Jung, J.Y.; Yang, S.H.; Lee, T.R.; Shin, D.W. Resveratrol induces autophagy through death-associated protein kinase 1 (dapk1) in human dermal fibroblasts under normal culture conditions. Exp. Dermatol. 2013, 22, 491–494.
196. Park, Y.Y.; Sohn, B.H.; Johnson, R.L.; Kang, M.H.; Kim, S.B.; Shim, J.J.; Mangala, L.S.; Kim, J.H.; Yoo, J.E.; Rodriguez-Aguayo, C. et al. Yes-associated protein 1 and transcriptional coactivator with pdz-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma. Hepatology 2016, 63, 159–172.
197. Eisenberg, T.; Knauer, H.; Schauer, A.; Buttner, S.; Ruckenstuhl, C.; Carmona-Gutierrez, D.; Ring, J.; Schroeder, S.; Magnes, C.; Antonacci, L. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 2009, 11, 1305–1314.
198. Pietrocola, F.; Lachkar, S.; Enot, D.P.; Niso-Santano, M.; Bravo-San Pedro, J.M.; Sica, V.; Izzo, V.; Maiuri, M.C.; Madeo, F.; Marino, G. et al. Spermidine induces autophagy by inhibiting the acetyltransferase ep300. Cell Death Differ. 2015, 22, 509–516.
199. Berger, Z.; Ravikumar, B.; Menzies, F.M.; Oroz, L.G.; Underwood, B.R.; Pangalos, M.N.; Schmitt, I.; Wullner, U.; Evert, B.O.; O’Kane, C.J. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 2006, 15, 433–442.
200. Spencer, B.; Potkar, R.; Trejo, M.; Rockenstein, E.; Patrick, C.; Gindi, R.; Adame, A.; Wyss-Coray, T.; Masliah, E. 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, 13578–13588.
201. Moors, T.E.; Hoozemans, J.J.; Ingrassia, A.; Beccari, T.; Parnetti, L.; Chartier-Harlin, M.C.; van de Berg, W.D. Therapeutic potential of autophagy-enhancing agents in parkinson’s disease. Mol. Neurodegener. 2017, 12, 11.
202. Martin, D.D.; Ladha, S.; Ehrnhoefer, D.E.; Hayden, M.R. Autophagy in huntington disease and huntingtin in autophagy. Trends Neurosci. 2015, 38, 26–35.
203. Rubinsztein, D.C.; Bento, C.F.; Deretic, V. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J. Exp. Med. 2015, 212, 979–990.
204. Majumder, S.; Richardson, A.; Strong, R.; Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 2011, 6, e25416.
205. Liang, J.H.; Jia, J.P. Dysfunctional autophagy in Alzheimer’s disease: Pathogenic roles and therapeutic implications. Neurosci. Bull. 2014, 30, 308–316.
206. 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. 2009, 16, 46–56.
207. Wang, I.F.; Guo, B.S.; Liu, Y.C.; Wu, C.C.; Yang, C.H.; Tsai, K.J.; Shen, C.K. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the tar DNA-binding protein 43. Proc. Natl. Acad. Sci. USA 2012, 109, 15024–15029.
208. Li, L.; Zhang, S.; Zhang, X.; Li, T.; Tang, Y.; Liu, H.; Yang, W.; Le, W. Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-beta pathology in a mouse model of Alzheimer’s disease. Curr. Alzheimer Res. 2013, 10, 433–441.
209. Jiang, T.; Yu, J.T.; Zhu, X.C.; Tan, M.S.; Wang, H.F.; Cao, L.; Zhang, Q.Q.; Shi, J.Q.; Gao, L.; Qin, H. et al. Temsirolimus promotes autophagic clearance of amyloid-beta and provides protective effects in cellular and animal models of Alzheimer’s disease. Pharmacol. Res. 2014, 81, 54–63.
210. Chu, C.; Zhang, X.; Ma, W.; Li, L.; Wang, W.; Shang, L.; Fu, P. Induction of autophagy by a novel small molecule improves abeta pathology and ameliorates cognitive deficits. PLoS ONE 2013, 8, e65367.
211. Tian, Y.; Bustos, V.; Flajolet, M.; Greengard, P. A small-molecule enhancer of autophagy decreases levels of abeta and app-ctf via atg5-dependent autophagy pathway. FASEB J. 2011, 25, 1934–1942.
212. Jin, F.; Wu, Q.; Lu, Y.F.; Gong, Q.H.; Shi, J.S. Neuroprotective effect of resveratrol on 6-ohda-induced parkinson’s disease in rats. Eur. J. Pharmacol. 2008, 600, 78–82.
213. Vidoni, C.; Secomandi, E.; Castiglioni, A.; Melone, M.A.B.; Isidoro, C. Resveratrol protects neuronal-like cells expressing mutant huntingtin from dopamine toxicity by rescuing atg4-mediated autophagosome formation. Neurochem. Int. 2017.
214. Hebron, M.L.; Lonskaya, I.; Moussa, C.E. 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, 3315–3328.
215. Yu, H.C.; Lin, C.S.; Tai, W.T.; Liu, C.Y.; Shiau, C.W.; Chen, K.F. Nilotinib induces autophagy in hepatocellular carcinoma through ampk activation. J. Biol. Chem. 2013, 288, 18249–18259.
216. Lonskaya, I.; Hebron, M.L.; Desforges, N.M.; Schachter, J.B.; Moussa, C.E. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J. Mol. Med. 2014, 92, 373–386.
217. Song, R. Mechanism of metformin: A tale of two sites. Diabetes Care 2016, 39, 187–189.
218. Ma, T.C.; Buescher, J.L.; Oatis, B.; Funk, J.A.; Nash, A.J.; Carrier, R.L.; Hoyt, K.R. Metformin therapy in a transgenic mouse model of huntington’s disease. Neurosci. Lett. 2007, 411, 98–103.
219. Haghani, M.; Shabani, M.; Tondar, M. The therapeutic potential of berberine against the altered intrinsic properties of the ca1 neurons induced by abeta neurotoxicity. Eur. J. Pharmacol. 2015, 758, 82–88.
220. Kim, M.; Cho, K.H.; Shin, M.S.; Lee, J.M.; Cho, H.S.; Kim, C.J.; Shin, D.H.; Yang, H.J. Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with parkinson’s disease. Int. J. Mol. Med. 2014, 33, 870–878.
221. Jiang, W.; Wei, W.; Gaertig, M.A.; Li, S.; Li, X.J. Therapeutic effect of berberine on huntington’s disease transgenic mouse model. PLoS ONE 2015, 10, e0134142.
222. Yu, R.; Zhang, Z.Q.; Wang, B.; Jiang, H.X.; Cheng, L.; Shen, L.M. Berberine-induced apoptotic and autophagic death of hepg2 cells requires ampk activation. Cancer Cell Int. 2014, 14, 49.
223. Rodriguez-Navarro, J.A.; Rodriguez, L.; Casarejos, M.J.; Solano, R.M.; Gomez, A.; Perucho, J.; Cuervo, A.M.; Garcia de Yebenes, J.; Mena, M.A. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol. Dis. 2010, 39, 423–438.
224. 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 alpha-synuclein. J. Biol. Chem. 2007, 282, 5641–5652.
225. Castillo, K.; Nassif, M.; Valenzuela, V.; Rojas, F.; Matus, S.; Mercado, G.; Court, F.A.; van Zundert, B.; Hetz, C. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 2013, 9, 1308–1320.
226. Feng, H.L.; Leng, Y.; Ma, C.H.; Zhang, J.; Ren, M.; Chuang, D.M. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 2008, 155, 567–572.
227. Zhang, X.; Heng, X.; Li, T.; Li, L.; Yang, D.; Du, Y.; Doody, R.S.; Le, W. Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer’s disease transgenic mouse model. J. Alzheimers Dis. 2011, 24, 739–749.
228. Fornai, F.; Longone, P.; Cafaro, L.; Kastsiuchenka, O.; Ferrucci, M.; Manca, M.L.; Lazzeri, G.; Spalloni, A.; Bellio, N.; Lenzi, P. et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 2008, 105, 2052–2057.
229. Pizzasegola, C.; Caron, I.; Daleno, C.; Ronchi, A.; Minoia, C.; Carri, M.T.; Bendotti, C. Treatment with lithium carbonate does not improve disease progression in two different strains of sod1 mutant mice. Amyotroph. Lateral Scler. 2009, 10, 221–228.
230. Sade, Y.; Toker, L.; Kara, N.Z.; Einat, H.; Rapoport, S.; Moechars, D.; Berry, G.T.; Bersudsky, Y.; Agam, G. Ip3 accumulation and/or inositol depletion: Two downstream lithium’s effects that may mediate its behavioral and cellular changes. Transl. Psychiatry 2016, 6, e968.
231. Sarkar, S.; Floto, R.A.; Berger, Z.; Imarisio, S.; Cordenier, A.; Pasco, M.; Cook, L.J.; Rubinsztein, D.C. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 2005, 170, 1101–1111.
232. 2+ transfer to mitochondria. Cell 2010, 142, 270–283.
233. Williams, A.; Sarkar, S.; Cuddon, P.; Ttofi, E.K.; Saiki, S.; Siddiqi, F.H.; Jahreiss, L.; Fleming, A.; Pask, D.; Goldsmith, P. et al. Novel targets for huntington’s disease in an mtor-independent autophagy pathway. Nat. Chem. Biol. 2008, 4, 295–305.
234. Sun, B.; Zhou, Y.; Halabisky, B.; Lo, I.; Cho, S.H.; Mueller-Steiner, S.; Devidze, N.; Wang, X.; Grubb, A.; Gan, L. Cystatin c-cathepsin b axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron 2008, 60, 247–257.