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Emerging Connections: Synaptic Autophagy in Brain Aging and Disease

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Autophagy in Health and Disease

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

The imbalance of proteostasis has been implicated in brain aging and neurodegenerative diseases. Therefore, clearing dysfunctional proteins and organelles in neurons via macroautophagy opens a new avenue to rejuvenate the protein pools and, thus, promotes synaptic and neuronal integrity and function. Evidence shows that autophagy is crucial in regulating neuronal development and maintaining neuronal integrity. Recent work has demonstrated that autophagosome formation is prominent at synaptic terminals, stimulating research interest in the process of synaptic autophagy. Furthermore, the roles for autophagosomes in transfering neuronal signaling during their retrograde transport to the soma, maintaining neuronal homeostasis and synaptic plasticity are beginning to emerge, yet we are only at the inception of our understanding of synapse-specific regulatory factors involved in synaptic autophagy. Hence, delineating interactions between synaptic cargoes and synaptic autophagy will provide a more comprehensive understanding of the roles for autophagy in maintaining neuronal function by regulating synaptic transmission and plasticity. In this chapter, I will briefly review how synaptic autophagy intersects with brain aging and disease.

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Abbreviations

AD:

Alzheimer’s disease

Alfy:

Autophagy linked FYVE protein

ALS:

Amyotrophic lateral sclerosis

Ambra1:

Activating molecule in Beclin1-regulated autophagy

AMI:

Age-induced memory impairment

ARM:

Anesthesia-resistant memory

ASD:

Autism spectrum disorders

ASM:

Anesthesia-sensitive memory

Aß:

Amyloid-ß

AZs:

Active zones

BDNF:

Brain-derived neurotrophic factor

CMA:

Chaperone-mediated autophagy

CNS:

Central nervous system

DR:

Dietary restriction

eIF5A:

Eukaryotic translation initiation factor 5A

FTLD:

Frontotemporal lobar degeneration

HD:

Huntington’s disease

HTT:

Huntingtin

MFRTA:

Mitochondrial free radical theory of aging

PD:

Parkinson’s disease

PN:

Proteostasis network

STED:

stimulated emission depletion

SV:

Synaptic vesicles

UPS:

Ubiquitin–proteasome system

References

  1. Armanios M, de Cabo R, Mannick J, Partridge L, van Deursen J, Villeda S. Translational strategies in aging and age-related disease. Nat Med. 2015;21(12):1395–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Granger A, Mott R, Emambokus N. Is aging as inevitable as death and taxes? Cell Metab. 2016;23(6):947–8.

    Article  CAS  PubMed  Google Scholar 

  3. Medvedecv AZ. An attempt at a rational classification of theories of ageing. Biol Rev. 1990;65(3):375–98.

    Article  Google Scholar 

  4. Stuart JA, Maddalena LA, Merilovich M, Robb EL. A midlife crisis for the mitochondrial free radical theory of aging. Longevity Healthspan. 2014;3(1):4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lapointe J, Hekimi S. When a theory of aging ages badly. Cell Mol Life Sci. 2010;67(1):1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barja G. Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxid Redox Signal. 2013;19(12):1420–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kirkwood TB. A systematic look at an old problem. Nature. 2010;451(7179):644–7.

    Article  CAS  Google Scholar 

  8. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Revuelta M, Matheu A. Autophagy in stem cell aging. Aging Cell. 2017;16(5):912–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem. 2009;78:959–91.

    Article  CAS  PubMed  Google Scholar 

  11. Sala AJ, Bott LC, Morimoto RI. Shaping proteostasis at the cellular, tissue, and organismal level. J Cell Biol. 2017;216(5):1231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Labbadia J, Morimoto RI. The biology of proteostasis in aging and disease. Annu Rev Biochem. 2015;84:435–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 2010;8(8):e1000450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell. 2010;143(5):813–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lim J, Yue Z. Neuronal aggregates: formation, clearance, and spreading. Dev Cell. 2015;32(4):491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schrimpf SP, Meskenaite V, Brunner E, Rutishauser D, Walther P, Eng J, Aebersold R, Sonderegger P. Proteomic analysis of synaptosomes using isotope-coded affinity tags and mass spectrometry. Proteomics. 2005;5(10):2531–41.

    Article  CAS  PubMed  Google Scholar 

  17. FM D, Birgit B, Stefan R, Larysa T, Giuseppina M, Turck CW. Profiling of mouse synaptosome proteome and phosphoproteome by IEF. Electrophoresis. 2010;31(8):1294–301.

    Article  CAS  Google Scholar 

  18. Flynn JM, Czerwieniec GA, Choi SW, Day NU, Gibson BW, Hubbard A, Melov S. Proteogenomics of synaptosomal mitochondrial oxidative stress. Free Radic Biol Med. 2012;53(5):1048–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Poon HF, Vaishnav RA, Getchell TV, Getchell ML, Butterfield DA. Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice. Neurobiol Aging. 2006;27(7):1010–9.

    Article  CAS  PubMed  Google Scholar 

  20. Mehan ND, Strauss KI. Combined age- and trauma-related proteomic changes in rat neocortex: a basis for brain vulnerability. Neurobiol Aging. 2012;33(9):1857–73.

    Article  CAS  PubMed  Google Scholar 

  21. Stauch KL, Purnell PR, Fox HS. Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic function. Aging. 2014;6(4):320–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang C, Telpoukhovskaia MA, Bahr BA, Chen X, Gan L. Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases. Curr Opin Neurobiol. 2018;48:52–8.

    Article  CAS  PubMed  Google Scholar 

  23. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.

    Article  CAS  PubMed  Google Scholar 

  24. Gao F, Yang J, Wang D, Li C, Fu Y, Wang H, He W, Zhang J. Mitophagy in Parkinson’s disease: pathogenic and therapeutic implications. Front Neurol. 2017;8:527.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Koyuncu S, Fatima A, Gutierrez-Garcia R, Vilchez D. Proteostasis of huntingtin in health and disease. Int J Mol Sci. 2017;18(7):pii: E1568.

    Article  Google Scholar 

  26. Harding RJ, Tong Y-F. Proteostasis in Huntington’s disease: disease mechanisms and therapeutic opportunities. Acta Pharmacol Sin. 2018;39:754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–11.

    Article  CAS  PubMed  Google Scholar 

  28. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(6):777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gotzl JK, Lang CM, Haass C, Capell A. Impaired protein degradation in FTLD and related disorders. Ageing Res Rev. 2016;32:122–39.

    Article  PubMed  CAS  Google Scholar 

  30. Nijholt DA, de Graaf TR, van Haastert ES, Oliveira AO, Berkers CR, Zwart R, Ovaa H, Baas F, Hoozemans JJ, Scheper W. Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ. 2011;18(6):1071–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morawe T, Hiebel C, Kern A, Behl C. Protein homeostasis, aging and Alzheimer’s disease. Mol Neurobiol. 2012;46(1):41–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Villemagne VL, Okamura N. Tau imaging in the study of ageing, Alzheimer’s disease, and other neurodegenerative conditions. Curr Opin Neurobiol. 2016;36:43–51.

    Article  CAS  PubMed  Google Scholar 

  33. Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J Cell Biol. 2018;217(1):51–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hering H, Sheng M. Dentritic spines: structure, dynamics and regulation. Nat Rev Neurosci. 2001;2:880.

    Article  CAS  PubMed  Google Scholar 

  35. Nimchinsky EA, Sabatini BL, Svoboda K. Structure and function of dendritic spines. Annu Rev Physiol. 2002;64:313–53.

    Article  CAS  PubMed  Google Scholar 

  36. Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014;344(6187):1023–8.

    Article  CAS  PubMed  Google Scholar 

  37. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012;75(5):762–77.

    Article  CAS  PubMed  Google Scholar 

  38. Wang YC, Lauwers E, Verstreken P. Presynaptic protein homeostasis and neuronal function. Curr Opin Genet Dev. 2017;44:38–46.

    Article  CAS  PubMed  Google Scholar 

  39. Liang Y, Sigrist S. Autophagy and proteostasis in the control of synapse aging and disease. Curr Opin Neurobiol. 2018;48:113–21.

    Article  CAS  PubMed  Google Scholar 

  40. Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn A-M, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313.

    Article  CAS  PubMed  Google Scholar 

  41. Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathern GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555(7696):377–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kaushik S, Cuervo AM. Proteostasis and aging. Nat Med. 2015;21(12):1406–15.

    Article  CAS  PubMed  Google Scholar 

  43. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41.

    Article  CAS  PubMed  Google Scholar 

  44. Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy. 2014;7(7):673–82.

    Article  CAS  Google Scholar 

  45. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22(8):407–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Jiang P, Mizushima N. Autophagy and human diseases. Cell Res. 2014;24(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  48. Choi AMK, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368(7):651–62.

    Article  CAS  PubMed  Google Scholar 

  49. Kroemer G. Autophagy: a druggable process that is deregulated in aging and human disease. J Clin Invest. 2015;125(1):1–4.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885–9.

    Article  CAS  PubMed  Google Scholar 

  51. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441(7095):880–4.

    Article  CAS  PubMed  Google Scholar 

  52. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447(7148):1121–5.

    CAS  PubMed  Google Scholar 

  53. Dragich JM, Kuwajima T, Hirose-Ikeda M, Yoon MS, Eenjes E, Bosco JR, Fox LM, Lystad AH, Oo TF, Yarygina O, Mita T, Waguri S, Ichimura Y, Komatsu M, Simonsen A, Burke RE, Mason CA, Yamamoto A. Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain. Elife. 2016;5:e14810.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):1131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoshii SR, Kuma A, Akashi T, Hara T, Yamamoto A, Kurikawa Y, Itakura E, Tsukamoto S, Shitara H, Eishi Y, Mizushima N. Systemic analysis of Atg5-Null mice rescued from neonatal lethality by transgenic ATG5 expression in neurons. Dev Cell. 2016;39(1):116–30.

    Article  CAS  PubMed  Google Scholar 

  56. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. 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 

  57. Yamamoto A, Yue Z. Autophagy and its normal and pathogenic states in the brain. Annu Rev Neurosci. 2014;37:55–78.

    Article  CAS  PubMed  Google Scholar 

  58. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 2017;93(5):1015–34.

    Article  CAS  PubMed  Google Scholar 

  59. Kim M, Ho A, Lee JH. Autophagy and human neurodegenerative diseases-a Fly’s perspective. Int J Mol Sci. 2017;18(7):pii: E1596.

    Article  Google Scholar 

  60. Ramesh N, Pandey UB. Autophagy dysregulation in ALS: when protein aggregates get out of hand. Front Mol Neurosci. 2017;10:263.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hars ES, Qi H, Jin SV, Cai L, Hu C, Liu LF. Autophagy regulates ageing in C. elegans. Autophagy. 2014;3(2):93–5.

    Article  Google Scholar 

  62. Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, Dipt S, Fiala A, Schenck A, Schwaerzel M, Madeo F, Sigrist SJ. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci. 2013;16(10):1453–60.

    Article  CAS  PubMed  Google Scholar 

  63. Lin FH, Zhang WL, Li H, Tian XD, Zhang J, Li X, Li CY, Tan JH. Role of autophagy in modulating post-maturation aging of mouse oocytes. Cell Death Dis. 2018;9(3):308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

  65. Perluigi M, Di Domenico F, Butterfield DA. mTOR signaling in aging and neurodegeneration: at the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis. 2015;84:39–49.

    Article  CAS  PubMed  Google Scholar 

  66. Yu Y, Feng L, Li J, Lan X, Lixiang A, Lv X, Zhang M, Chen L. The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits. Behav Brain Res. 2017;334:155–62.

    Article  CAS  PubMed  Google Scholar 

  67. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci. 2010;107(32):14164–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alirezaei M, Kiosses WB, Flynn CT, Brady NR, Fox HS. Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One. 2008;3(8):e2906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Gan L, Vargas MR, Johnson DA, Johnson JA. Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci. 2012;32(49):17775–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Madill M, McDonagh K, Ma J, Vajda A, McLoughlin P, O’Brien T, Hardiman O, Shen S. Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms. Mol Brain. 2017;10(1):22.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Davis CH, Kim KY, Bushong EA, Mills EA, Boassa D, Shih T, Kinebuchi M, Phan S, Zhou Y, Bihlmeyer NA, Nguyen JV, Jin Y, Ellisman MH, Marsh-Armstrong N. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A. 2014;111(26):9633–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Melentijevic I, Toth ML, Arnold ML, Guasp RJ, Harinath G, Nguyen KC, Taub D, Parker JA, Neri C, Gabel CV, Hall DH, Driscoll M. C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature. 2017;542(7641):367–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kulkarni A, Chen J, Maday S. Neuronal autophagy and intercellular regulation of homeostasis in the brain. Curr Opin Neurobiol. 2018;51:29–36.

    Article  CAS  PubMed  Google Scholar 

  74. Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy. 2014;4(2):176–84.

    Article  Google Scholar 

  75. Juhasz G, Erdi B, Sass M, Neufeld TP. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev. 2007;21(23):3061–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014;157(7):1515–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Luo L, Dai JR, Guo SS, Lu AM, Gao XF, Gu YR, Zhang XF, Xu HD, Wang Y, Zhu Z, Wood LJ, Qin ZH. Lysosomal proteolysis is associated with exercise-induced improvement of mitochondrial quality control in aged hippocampus. J Gerontol A Biol Sci Med Sci. 2017;72:1342.

    Article  PubMed  Google Scholar 

  78. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. King MA, Hands S, Hafiz F, Mizushima N, Tolkovsky AM, Wyttenbach A. Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis. Mol Pharmacol. 2008;73(4):1052–63.

    Article  CAS  PubMed  Google Scholar 

  81. Wyttenbach A, Hands S, King MA, Lipkow K, Tolkovsky AM. Amelioration of protein misfolding disease by rapamycin: translation or autophagy? Autophagy. 2008;4(4):542–5.

    Article  CAS  PubMed  Google Scholar 

  82. Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience. 2012;223:102–13.

    Article  CAS  PubMed  Google Scholar 

  83. Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014;19(3):373–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Frohlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305–14.

    Article  CAS  PubMed  Google Scholar 

  85. Madeo F, Eisenberg T, Büttner S, Ruckenstuhl C, Kroemer G. Spermidine: a novel autophagy inducer and longevity elixir. Autophagy. 2010;6(1):160–2.

    Article  PubMed  Google Scholar 

  86. Morselli E, Marino G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, Cabrera S, Benit P, Rustin P, Criollo A, Kepp O, Galluzzi L, Shen S, Malik SA, Maiuri MC, Horio Y, Lopez-Otin C, Andersen JS, Tavernarakis N, Madeo F, Kroemer G. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol. 2011;192(4):615–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lubas M, Harder LM, Kumsta C, Tiessen I, Hansen M, Andersen JS, Lund AH, Frankel LB. eIF5A is required for autophagy by mediating ATG3 translation. EMBO Rep. 2018;19(6):pii: e46072.

    Article  CAS  Google Scholar 

  88. Wolff EC, Kang KR, Kim YS, Park MH. Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification. Amino Acids. 2007;33(2):341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Margulies C, Tully T, Dubnau J. Deconstructing memory in Drosophila. Curr Biol. 2005;15(17):R700–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Saitoe M, Horiuchi J, Tamura T, Ito N. Drosophila as a novel animal model for studying the genetics of age-related memory impairment. Rev Neurosci. 2005;16(2):137–50.

    Article  CAS  PubMed  Google Scholar 

  91. Tonoki A, Davis RL. Aging impairs intermediate-term behavioral memory by disrupting the dorsal paired medial neuron memory trace. Proc Natl Acad Sci U S A. 2012;109(16):6319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Murakami S, Minami-Ohtsubo M, Nakato R, Shirahige K, Tabata T. Two components of aversive memory in Drosophila, anesthesia-sensitive and anesthesia-resistant memory, require distinct domains within the Rgk1 small GTPase. J Neurosci. 2017;37(22):5496–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tamura T, Chiang A-S, Ito N, Liu H-P, Horiuchi J, Tully T, Saitoe M. Aging specifically impairs amnesiac-dependent memory in Drosophila. Neuron. 2003;40(5):1003–11.

    Article  CAS  PubMed  Google Scholar 

  94. Takeuchi T, Duszkiewicz AJ, Morris RG. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2014;369(1633):20130288.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Petzoldt AG, Lutzkendorf J, Sigrist SJ. Mechanisms controlling assembly and plasticity of presynaptic active zone scaffolds. Curr Opin Neurobiol. 2016;39:69–76.

    Article  CAS  PubMed  Google Scholar 

  96. Gupta VK, Pech U, Bhukel A, Fulterer A, Ender A, Mauermann SF, Andlauer TF, Antwi-Adjei E, Beuschel C, Thriene K, Maglione M, Quentin C, Bushow R, Schwarzel M, Mielke T, Madeo F, Dengjel J, Fiala A, Sigrist SJ. Spermidine suppresses age-associated memory impairment by preventing adverse increase of presynaptic active zone size and release. PLoS Biol. 2016;14(9):e1002563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Bhukel A, Madeo F, Sigrist SJ. Spermidine boosts autophagy to protect from synapse aging. Autophagy. 2017;13(2):444–5.

    Article  CAS  PubMed  Google Scholar 

  98. Soukup SF, Kuenen S, Vanhauwaert R, Manetsberger J, Hernandez-Diaz S, Swerts J, Schoovaerts N, Vilain S, Gounko NV, Vints K, Geens A, De Strooper B, Verstreken P. A LRRK2-dependent EndophilinA phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron. 2016;92(4):829–44.

    Article  CAS  PubMed  Google Scholar 

  99. Vanhauwaert R, Kuenen S, Masius R, Bademosi A, Manetsberger J, Schoovaerts N, Bounti L, Gontcharenko S, Swerts J, Vilain S, Picillo M, Barone P, Munshi ST, de Vrij FM, Kushner SA, Gounko NV, Mandemakers W, Bonifati V, Meunier FA, Soukup SF, Verstreken P. The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. EMBO J. 2017;36:1392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Okerlund ND, Schneider K, Leal-Ortiz S, Montenegro-Venegas C, Kim SA, Garner LC, Gundelfinger ED, Reimer RJ, Garner CC. Bassoon controls presynaptic autophagy through Atg5. Neuron. 2017;93(4):897–913.e897.

    Article  CAS  PubMed  Google Scholar 

  101. Binotti B, Pavlos NJ, Riedel D, Wenzel D, Vorbruggen G, Schalk AM, Kuhnel K, Boyken J, Erck C, Martens H, Chua JJ, Jahn R. The GTPase Rab26 links synaptic vesicles to the autophagy pathway. Elife. 2015;4:e05597.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol. 2003;161(3):609–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Uytterhoeven V, Kuenen S, Kasprowicz J, Miskiewicz K, Verstreken P. Loss of skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell. 2011;145(1):117–32.

    Article  CAS  PubMed  Google Scholar 

  104. Rowland AM, Richmond JE, Olsen JG, Hall DH, Bamber BA. Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. J Neurosci. 2006;26(6):1711–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J Neurosci. 2012;32(30):10413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nikoletopoulou V, Sidiropoulou K, Kallergi E, Dalezios Y, Tavernarakis N. Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab. 2017;26(1):230–242.e235.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Cai Q, Zakaria HM, Simone A, Sheng ZH. Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons. Curr Biol. 2012;22(6):545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sung H, Tandarich LC, Nguyen K, Hollenbeck PJ. Compartmentalized regulation of Parkin-mediated mitochondrial quality control in the Drosophila nervous system in vivo. J Neurosci. 2016;36(28):7375–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014;206(5):655–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cao X, Wang H, Wang Z, Wang Q, Zhang S, Deng Y, Fang Y. In vivo imaging reveals mitophagy independence in the maintenance of axonal mitochondria during normal aging. Aging Cell. 2017;16(5):1180–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pickles S, Vigie P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):R170–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Maday S, Wallace KE, Holzbaur EL. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol. 2012;196(4):407–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang T, Martin S, Papadopulos A, Harper CB, Mavlyutov TA, Niranjan D, Glass NR, Cooper-White JJ, Sibarita JB, Choquet D, Davletov B, Meunier FA. Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a. J Neurosci. 2015;35(15):6179–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Stavoe AK, Hill SE, Hall DH, Colon-Ramos DA. KIF1A/UNC-104 transports ATG-9 to regulate neurodevelopment and autophagy at synapses. Dev Cell. 2016;38(2):171–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. 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  CAS  PubMed  PubMed Central  Google Scholar 

  118. Maday S, Holzbaur EL. Compartment-specific regulation of autophagy in primary neurons. J Neurosci. 2016;36(22):5933–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tsvetkov AS, Miller J, Arrasate M, Wong JS, Pleiss MA, Finkbeiner S. A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A. 2010;107(39):16982–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fox JH, Connor T, Chopra V, Dorsey K, Kama JA, Bleckmann D, Betschart C, Hoyer D, Frentzel S, Difiglia M, Paganetti P, Hersch SM. The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington’s disease. Mol Neurodegener. 2010;5:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Shen W, Ganetzky B. Autophagy promotes synapse development in Drosophila. J Cell Biol. 2009;187(1):71–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kononenko NL, Classen GA, Kuijpers M, Puchkov D, Maritzen T, Tempes A, Malik AR, Skalecka A, Bera S, Jaworski J, Haucke V. Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nat Commun. 2017;8:14819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Burk K, Murdoch JD, Freytag S, Koenig M, Bharat V, Markworth R, Burkhardt S, Fischer A, Dean C. EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons. Sci Rep. 2017;7(1):2149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Wu CL, Chen CH, Hwang CS, Chen SD, Hwang WC, Yang DI. Roles of p62 in BDNF-dependent autophagy suppression and neuroprotection against mitochondrial dysfunction in rat cortical neurons. J Neurochem. 2017;140(6):845–61.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

I am deeply indebted to Stephan Sigrist for helpful discussion and resources. This work was supported by SFB958 of the Deutsche Forschungsgemeinschaft (DFG) and the China Scholarship Council (CSC).

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Authors and Affiliations

  1. Institute of Biology/Genetics, Freie Universität Berlin, Berlin, Germany

    YongTian Liang

  2. NeuroCure, Cluster of Excellence, Charité Universitätmedizin, Berlin, Germany

    YongTian Liang

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  1. Ottawa, ON, Canada

    Kursad Turksen

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Liang, Y. (2018). Emerging Connections: Synaptic Autophagy in Brain Aging and Disease. In: Turksen, K. (eds) Autophagy in Health and Disease. Stem Cell Biology and Regenerative Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-98146-8_9

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