Skip to content
2000
image of The Fragile Balance: Autophagy's Role in Neurodegenerative Disease Progression

Abstract

Autophagy relates to the mechanism underlying the intracellular constituents’ breakdown by lysosomes. Autophagy plays an essential role in preserving and regulating cellular homeostasis by mediating the degradation of intracellular components and recycling their decomposition products. It was demonstrated that autophagy operates in the starving reaction, initial growth, internal control of quality, and cell division. Autophagy malfunction is perhaps connected with cancer and neurological conditions, as demonstrated by current research. In conjunction with the identification of specific mutations associated with autophagy-related disorders and deeper knowledge of the pathophysiology of disorders caused by aberrant disintegration of particular autophagy substrates, autophagy activation serves a vital part in prolonging lifespans and suppressing the process of aging. To safeguard the homeostasis within a cell, cells have developed sophisticated quality-control procedures for organelles and proteins. These quality-control mechanisms maintain cellular integrity through degradation by the autophagy-lysosome or ubiquitin-proteasome systems, as well as through protein folding assistance (or refolding of misfolded proteins) provided by molecular chaperones. A great deal of neurodegenerative illnesses are indicated by the development of intracellular inclusions formed from misfolded proteins, which are believed to be an outcome of defective autophagy. Additionally, it was recently discovered that neurodegenerative illnesses are also linked with mutations in key autophagy-related genes. However, pathogenic proteins like α-synuclein and amyloid β cause damage to the autophagy system. This paper examines the recent advancements in our understanding of the link between autophagic abnormalities and the development of neurological disorders, and proposes that activating autophagy could serve as a potential therapeutic strategy.

Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X377552250627113915
2025-07-03
2025-09-13
Loading full text...

Full text loading...

References

  1. de Duve C. Pressman B.C. Gianetto R. Wattiaux R. Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 1955 60 4 604 617 10.1042/bj0600604 13249955
    [Google Scholar]
  2. Burman C. Ktistakis N.T. Autophagosome formation in mammalian cells. Semin. Immunopathol. 2010 32 4 397 413 10.1007/s00281‑010‑0222‑z 20740284
    [Google Scholar]
  3. Tasset I. Cuervo A.M. Role of chaperone‐mediated autophagy in metabolism. FEBS J. 2016 283 13 2403 2413 10.1111/febs.13677 26854402
    [Google Scholar]
  4. Li W. Li J. Bao J. Microautophagy: Lesser-known self-eating. Cell. Mol. Life Sci. 2012 69 7 1125 1136 10.1007/s00018‑011‑0865‑5 22080117
    [Google Scholar]
  5. Li L. Tan J. Miao Y. Lei P. Zhang Q. ROS and autophagy: Interactions and molecular regulatory mechanisms. Cell. Mol. Neurobiol. 2015 35 5 615 621 10.1007/s10571‑015‑0166‑x 25722131
    [Google Scholar]
  6. Meléndez A. Tallóczy Z. Seaman M. Eskelinen E.L. Hall D.H. Levine B. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003 301 5638 1387 1391 10.1126/science.1087782 12958363
    [Google Scholar]
  7. Uddin M.N. Nishio N. Ito S. Suzuki H. Isobe K. Autophagic activity in thymus and liver during aging. Age 2012 34 1 75 85 10.1007/s11357‑011‑9221‑9 21387084
    [Google Scholar]
  8. Di Nardo A. Wertz M.H. Kwiatkowski E. Tsai P.T. Leech J.D. Greene-Colozzi E. Goto J. Dilsiz P. Talos D.M. Clish C.B. Kwiatkowski D.J. Sahin M. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum. Mol. Genet. 2014 23 14 3865 3874 10.1093/hmg/ddu101 24599401
    [Google Scholar]
  9. Jang M. Park R. Kim H. Namkoong S. Jo D. Huh Y.H. Jang I.S. Lee J.I. Park J. AMPK contributes to autophagosome maturation and lysosomal fusion. Sci. Rep. 2018 8 1 12637 10.1038/s41598‑018‑30977‑7 30140075
    [Google Scholar]
  10. Turco E. Fracchiolla D. Martens S. Recruitment and activation of the ULK1/Atg1 kinase complex in selective autophagy. J. Mol. Biol. 2020 432 1 123 134 10.1016/j.jmb.2019.07.027 31351898
    [Google Scholar]
  11. Park J.M. Seo M. Jung C.H. Grunwald D. Stone M. Otto N.M. Toso E. Ahn Y. Kyba M. Griffin T.J. Higgins L. Kim D.H. ULK1 phosphorylates Ser30 of BECN1 in association with ATG14 to stimulate autophagy induction. Autophagy 2018 14 4 584 597 10.1080/15548627.2017.1422851 29313410
    [Google Scholar]
  12. Puri C. Vicinanza M. Ashkenazi A. Gratian M.J. Zhang Q. Bento C.F. Renna M. Menzies F.M. Rubinsztein D.C. The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A. Dev. Cell 2018 45 1 114 131.e8 10.1016/j.devcel.2018.03.008 29634932
    [Google Scholar]
  13. Mizushima N. Sugita H. Yoshimori T. Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 1998 273 51 33889 33892 10.1074/jbc.273.51.33889 9852036
    [Google Scholar]
  14. Lystad A.H. Carlsson S.R. de la Ballina L.R. Kauffman K.J. Nag S. Yoshimori T. Melia T.J. Simonsen A. Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes. Nat. Cell Biol. 2019 21 3 372 383 10.1038/s41556‑019‑0274‑9 30778222
    [Google Scholar]
  15. Satoo K. Noda N.N. Kumeta H. Fujioka Y. Mizushima N. Ohsumi Y. Inagaki F. The structure of Atg4B–LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009 28 9 1341 1350 10.1038/emboj.2009.80 19322194
    [Google Scholar]
  16. Martens S. Nakamura S. Yoshimori T. Phospholipids in autophagosome formation and fusion. J. Mol. Biol. 2016 428 24 4819 4827 10.1016/j.jmb.2016.10.029 27984040
    [Google Scholar]
  17. Popovic D. Dikic I. TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep. 2014 15 4 392 401 10.1002/embr.201337995 24603492
    [Google Scholar]
  18. Imai K. Hao F. Fujita N. Tsuji Y. Oe Y. Araki Y. Hamasaki M. Noda T. Yoshimori T. Atg9A trafficking through the recycling endosomes is required for autophagosome formation. J. Cell Sci. 2016 129 20 3781 3791 10.1242/jcs.196196 27587839
    [Google Scholar]
  19. Chowdhury S. Otomo C. Leitner A. Ohashi K. Aebersold R. Lander G.C. Otomo T. Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex. Proc. Natl. Acad. Sci. USA 2018 115 42 E9792 E9801 10.1073/pnas.1811874115 30185561
    [Google Scholar]
  20. Osawa T. Kotani T. Kawaoka T. Hirata E. Suzuki K. Nakatogawa H. Ohsumi Y. Noda N.N. Atg2 mediates direct lipid transfer between membranes for autophagosome formation. Nat. Struct. Mol. Biol. 2019 26 4 281 288 10.1038/s41594‑019‑0203‑4 30911189
    [Google Scholar]
  21. Zhou F. Zou S. Chen Y. Lipatova Z. Sun D. Zhu X. Li R. Wu Z. You W. Cong X. Zhou Y. Xie Z. Gyurkovska V. Liu Y. Li Q. Li W. Cheng J. Liang Y. Segev N.A. Rab5 GTPase module is important for autophagosome closure. PLoS Genet. 2017 13 9 1007020 10.1371/journal.pgen.1007020 28934205
    [Google Scholar]
  22. Nakamura S. Yoshimori T. New insights into autophagosome–lysosome fusion. J. Cell Sci. 2017 130 7 1209 1216 10.1242/jcs.196352 28302910
    [Google Scholar]
  23. Wong Y.C. Holzbaur E.L.F. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 2014 34 4 1293 1305 10.1523/JNEUROSCI.1870‑13.2014 24453320
    [Google Scholar]
  24. Cheng X.T. Zhou B. Lin M.Y. Cai Q. Sheng Z.H. Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes. J. Cell Biol. 2015 209 3 377 386 10.1083/jcb.201412046 25940348
    [Google Scholar]
  25. Itakura E. Kishi-Itakura C. Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 2012 151 6 1256 1269 10.1016/j.cell.2012.11.001 23217709
    [Google Scholar]
  26. Yu L. McPhee C.K. Zheng L. Mardones G.A. Rong Y. Peng J. Mi N. Zhao Y. Liu Z. Wan F. Hailey D.W. Oorschot V. Klumperman J. Baehrecke E.H. Lenardo M.J. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010 465 7300 942 946 10.1038/nature09076 20526321
    [Google Scholar]
  27. Rong Y. Liu M. Ma L. Du W. Zhang H. Tian Y. Cao Z. Li Y. Ren H. Zhang C. Li L. Chen S. Xi J. Yu L. Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation. Nat. Cell Biol. 2012 14 9 924 934 10.1038/ncb2557 22885770
    [Google Scholar]
  28. Schulze R.J. Weller S.G. Schroeder B. Krueger E.W. Chi S. Casey C.A. McNiven M.A. Lipid droplet breakdown requires Dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J. Cell Biol. 2013 203 2 315 326 10.1083/jcb.201306140 24145164
    [Google Scholar]
  29. Mizushima N. Komatsu M. Autophagy: Renovation of cells and tissues. Cell 2011 147 4 728 741 10.1016/j.cell.2011.10.026 22078875
    [Google Scholar]
  30. Scrivo A. Bourdenx M. Pampliega O. Cuervo A.M. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol. 2018 17 9 802 815 10.1016/S1474‑4422(18)30238‑2 30129476
    [Google Scholar]
  31. Conway O. Akpinar H.A. Rogov V.V. Kirkin V. Selective autophagy receptors in neuronal health and disease. J. Mol. Biol. 2020 432 8 2483 2509 10.1016/j.jmb.2019.10.013 31654670
    [Google Scholar]
  32. Zaffagnini G. Savova A. Danieli A. Romanov J. Tremel S. Ebner M. Peterbauer T. Sztacho M. Trapannone R. Tarafder A.K. Sachse C. Martens S. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 2018 37 5 98308 10.15252/embj.201798308 29343546
    [Google Scholar]
  33. Suzuki N. Rohaim A. Kato R. Dikic I. Wakatsuki S. Kawasaki M. A novel mode of ubiquitin recognition by the ubiquitin‐binding zinc finger domain of WRNIP 1. FEBS J. 2016 283 11 2004 2017 10.1111/febs.13734 27062441
    [Google Scholar]
  34. Rogov V.V. Stolz A. Ravichandran A.C. Rios-Szwed D.O. Suzuki H. Kniss A. Löhr F. Wakatsuki S. Dötsch V. Dikic I. Dobson R.C.J. McEwan D.G. Structural and functional analysis of the GABARAP interaction motif (GIM). EMBO Rep. 2017 18 8 1382 1396 10.15252/embr.201643587 28655748
    [Google Scholar]
  35. Maiuri M.C. Zalckvar E. Kimchi A. Kroemer G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 2007 8 9 741 752 10.1038/nrm2239 17717517
    [Google Scholar]
  36. Bursch W. The autophagosomal–lysosomal compartment in programmed cell death. Cell Death Differ. 2001 8 6 569 581 10.1038/sj.cdd.4400852 11536007
    [Google Scholar]
  37. González-Polo R.A. Boya P. Pauleau A.L. Jalil A. Larochette N. Souquère S. Eskelinen E.L. Pierron G. Saftig P. Kroemer G. The apoptosis/autophagy paradox: Autophagic vacuolization before apoptotic death. J. Cell Sci. 2005 118 14 3091 3102 10.1242/jcs.02447 15985464
    [Google Scholar]
  38. Gustafsson Å.B. Gottlieb R.A. Recycle or die: The role of autophagy in cardioprotection. J. Mol. Cell. Cardiol. 2008 44 4 654 661 10.1016/j.yjmcc.2008.01.010 18353358
    [Google Scholar]
  39. Pattingre S. Tassa A. Qu X. Garuti R. Liang X.H. Mizushima N. Packer M. Schneider M.D. Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005 122 6 927 939 10.1016/j.cell.2005.07.002 16179260
    [Google Scholar]
  40. Djavaheri-Mergny M. Maiuri M.C. Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 2010 29 12 1717 1719 10.1038/onc.2009.519 20101204
    [Google Scholar]
  41. Pyo J.O. Jang M.H. Kwon Y.K. Lee H.J. Jun J.I.L. Woo H.N. Cho D.H. Choi B. Lee H. Kim J.H. Mizushima N. Oshumi Y. Jung Y.K. Essential roles of Atg5 and FADD in autophagic cell death: Dissection of autophagic cell death into vacuole formation and cell death. J. Biol. Chem. 2005 280 21 20722 20729 10.1074/jbc.M413934200 15778222
    [Google Scholar]
  42. Sui X. Chen R. Wang Z. Huang Z. Kong N. Zhang M. Han W. Lou F. Yang J. Zhang Q. Wang X. He C. Pan H. Autophagy and chemotherapy resistance: A promising therapeutic target for cancer treatment. Cell Death Dis. 2013 4 10 838 10.1038/cddis.2013.350 24113172
    [Google Scholar]
  43. Ginet V. Puyal J. Clarke P.G.H. Truttmann A.C. Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms. Am. J. Pathol. 2009 175 5 1962 1974 10.2353/ajpath.2009.090463 19815706
    [Google Scholar]
  44. Zaffagnini G. Martens S. Mechanisms of selective autophagy. J. Mol. Biol. 2016 428 9 1714 1724 10.1016/j.jmb.2016.02.004 26876603
    [Google Scholar]
  45. Rogov V. Dötsch V. Johansen T. Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 2014 53 2 167 178 10.1016/j.molcel.2013.12.014 24462201
    [Google Scholar]
  46. Ichimura Y. Waguri S. Sou Y. Kageyama S. Hasegawa J. Ishimura R. Saito T. Yang Y. Kouno T. Fukutomi T. Hoshii T. Hirao A. Takagi K. Mizushima T. Motohashi H. Lee M.S. Yoshimori T. Tanaka K. Yamamoto M. Komatsu M. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol. Cell 2013 51 5 618 631 10.1016/j.molcel.2013.08.003 24011591
    [Google Scholar]
  47. Nunnari J. Suomalainen A. Mitochondria: In sickness and in health. Cell 2012 148 6 1145 1159 10.1016/j.cell.2012.02.035 22424226
    [Google Scholar]
  48. Choudhury A.R. Singh K.K. Mitochondrial determinants of cancer health disparities. Semin. Cancer Biol. 2017 47 125 146 10.1016/j.semcancer.2017.05.001 28487205
    [Google Scholar]
  49. Chourasia A.H. Tracy K. Frankenberger C. Boland M.L. Sharifi M.N. Drake L.E. Sachleben J.R. Asara J.M. Locasale J.W. Karczmar G.S. Macleod K.F. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep. 2015 16 9 1145 1163 10.15252/embr.201540759 26232272
    [Google Scholar]
  50. Scorziello A. Borzacchiello D. Sisalli M.J. Di Martino R. Morelli M. Feliciello A. Mitochondrial homeostasis and signaling in parkinson’s disease. Front. Aging Neurosci. 2020 12 100 10.3389/fnagi.2020.00100 32372945
    [Google Scholar]
  51. Sato M. Sato K. Tomura K. Kosako H. Sato K. The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans. Nat. Cell Biol. 2018 20 1 81 91 10.1038/s41556‑017‑0008‑9 29255173
    [Google Scholar]
  52. Rojansky R. Cha M.Y. Chan D.C. Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife 2016 5 17896 10.7554/eLife.17896 27852436
    [Google Scholar]
  53. Schwarz D.S. Blower M.D. The endoplasmic reticulum: Structure, function and response to cellular signaling. Cell. Mol. Life Sci. 2016 73 1 79 94 10.1007/s00018‑015‑2052‑6 26433683
    [Google Scholar]
  54. Khaminets A. Heinrich T. Mari M. Grumati P. Huebner A.K. Akutsu M. Liebmann L. Stolz A. Nietzsche S. Koch N. Mauthe M. Katona I. Qualmann B. Weis J. Reggiori F. Kurth I. Hübner C.A. Dikic I. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 2015 522 7556 354 358 10.1038/nature14498 26040720
    [Google Scholar]
  55. Peng Y. Shapiro S.L. Banduseela V.C. Dieterich I.A. Hewitt K.J. Bresnick E.H. Kong G. Zhang J. Schueler K.L. Keller M.P. Attie A.D. Hacker T.A. Sullivan R. Kielar-Grevstad E. Arriola Apelo S.I. Lamming D.W. Anderson R.M. Puglielli L. Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype. Aging Cell 2018 17 5 12820 10.1111/acel.12820 30051577
    [Google Scholar]
  56. Radulovic M. Schink K.O. Wenzel E.M. Nähse V. Bongiovanni A. Lafont F. Stenmark H. ESCRT ‐mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 2018 37 21 99753 10.15252/embj.201899753 30314966
    [Google Scholar]
  57. Maejima I. Takahashi A. Omori H. Kimura T. Takabatake Y. Saitoh T. Yamamoto A. Hamasaki M. Noda T. Isaka Y. Yoshimori T. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 2013 32 17 2336 2347 10.1038/emboj.2013.171 23921551
    [Google Scholar]
  58. Dou Z. Xu C. Donahue G. Shimi T. Pan J.A. Zhu J. Ivanov A. Capell B.C. Drake A.M. Shah P.P. Catanzaro J.M. Daniel Ricketts M. Lamark T. Adam S.A. Marmorstein R. Zong W.X. Johansen T. Goldman R.D. Adams P.D. Berger S.L. Autophagy mediates degradation of nuclear lamina. Nature 2015 527 7576 105 109 10.1038/nature15548 26524528
    [Google Scholar]
  59. Zhang J. Tripathi D.N. Jing J. Alexander A. Kim J. Powell R.T. Dere R. Tait-Mulder J. Lee J.H. Paull T.T. Pandita R.K. Charaka V.K. Pandita T.K. Kastan M.B. Walker C.L. ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat. Cell Biol. 2015 17 10 1259 1269 10.1038/ncb3230 26344566
    [Google Scholar]
  60. Yamashita S. Abe K. Tatemichi Y. Fujiki Y. The membrane peroxin PEX3 induces peroxisome-ubiquitination-linked pexophagy. Autophagy 2014 10 9 1549 1564 10.4161/auto.29329 25007327
    [Google Scholar]
  61. Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism. Nature 2009 458 7242 1131 1135 10.1038/nature07976 19339967
    [Google Scholar]
  62. Ichimiya T. Yamakawa T. Hirano T. Yokoyama Y. Hayashi Y. Hirayama D. Wagatsuma K. Itoi T. Nakase H. Autophagy and autophagy-related diseases: A review. Int. J. Mol. Sci. 2020 21 23 8974 10.3390/ijms21238974 33255983
    [Google Scholar]
  63. Choy A. Dancourt J. Mugo B. O’Connor T.J. Isberg R.R. Melia T.J. Roy C.R. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 2012 338 6110 1072 1076 10.1126/science.1227026 23112293
    [Google Scholar]
  64. De S. Wirthensohn D.C. Flagmeier P. Hughes C. Aprile F.A. Ruggeri F.S. Whiten D.R. Emin D. Xia Z. Varela J.A. Sormanni P. Kundel F. Knowles T.P.J. Dobson C.M. Bryant C. Vendruscolo M. Klenerman D. Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms. Nat. Commun. 2019 10 1 1541 10.1038/s41467‑019‑09477‑3 30948723
    [Google Scholar]
  65. Wyant G.A. Abu-Remaileh M. Frenkel E.M. Laqtom N.N. Dharamdasani V. Lewis C.A. Chan S.H. Heinze I. Ori A. Sabatini D.M. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science 2018 360 6390 751 758 10.1126/science.aar2663 29700228
    [Google Scholar]
  66. Lee C.W. Wilfling F. Ronchi P. Allegretti M. Mosalaganti S. Jentsch S. Beck M. Pfander B. Selective autophagy degrades nuclear pore complexes. Nat. Cell Biol. 2020 22 2 159 166 10.1038/s41556‑019‑0459‑2 32029894
    [Google Scholar]
  67. Fujiwara Y. Kikuchi H. Aizawa S. Furuta A. Hatanaka Y. Konya C. Uchida K. Wada K. Kabuta T. Direct uptake and degradation of DNA by lysosomes. Autophagy 2013 9 8 1167 1171 10.4161/auto.24880 23839276
    [Google Scholar]
  68. Nguyen T.A. Bieging-Rolett K.T. Putoczki T.L. Wicks I.P. Attardi L.D. Pang K.C. SIDT2 RNA transporter promotes lung and gastrointestinal tumor development. iScience 2019 20 14 24 10.1016/j.isci.2019.09.009 31546103
    [Google Scholar]
  69. Kesidou E. Lagoudaki R. Touloumi O. Poulatsidou K.N. Simeonidou C. Autophagy and neurodegenerative disorders. Neural Regen. Res. 2013 8 24 2275 2283 25206537
    [Google Scholar]
  70. Millecamps S. Julien J.P. Axonal transport deficits and neurodegenerative diseases. Nat. Rev. Neurosci. 2013 14 3 161 176 10.1038/nrn3380 23361386
    [Google Scholar]
  71. Menzies F.M. Fleming A. Caricasole A. Bento C.F. Andrews S.P. Ashkenazi A. Füllgrabe 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 D.C. Autophagy and neurodegeneration: Pathogenic mechanisms and therapeutic opportunities. Neuron 2017 93 5 1015 1034 10.1016/j.neuron.2017.01.022 28279350
    [Google Scholar]
  72. Deng Z. Purtell K. Lachance V. Wold M.S. Chen S. Yue Z. Autophagy receptors and neurodegenerative diseases. Trends Cell Biol. 2017 27 7 491 504 10.1016/j.tcb.2017.01.001 28169082
    [Google Scholar]
  73. Ravikumar B. Duden R. Rubinsztein D.C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 2002 11 9 1107 1117 10.1093/hmg/11.9.1107 11978769
    [Google Scholar]
  74. Tsvetkov A.S. Arrasate M. Barmada S. Ando D.M. Sharma P. Shaby B.A. Finkbeiner S. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat. Chem. Biol. 2013 9 9 586 592 10.1038/nchembio.1308 23873212
    [Google Scholar]
  75. Waldemar G. Dubois B. Emre M. Georges J. McKeith I.G. Rossor M. Scheltens P. Tariska P. Winblad B. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur. J. Neurol. 2007 14 1 e1 e26 10.1111/j.1468‑1331.2006.01605.x 17222085
    [Google Scholar]
  76. Wang J.Z. Xia Y.Y. Grundke-Iqbal I. Iqbal K. Abnormal hyperphosphorylation of tau: Sites, regulation, and molecular mechanism of neurofibrillary degeneration. J. Alzheimers Dis. 2012 33 s1 S123 S139 10.3233/JAD‑2012‑129031 22710920
    [Google Scholar]
  77. 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 2 113 122 10.1093/jnen/64.2.113 15751225
    [Google Scholar]
  78. Ułamek-Kozioł M. Furmaga-Jabłońska W. Januszewski S. Brzozowska J. Ściślewska M. Jabłoński M. Pluta R. Neuronal autophagy: Self-eating or self-cannibalism in Alzheimer’s disease. Neurochem. Res. 2013 38 9 1769 1773 10.1007/s11064‑013‑1082‑4 23737325
    [Google Scholar]
  79. Nah J. Pyo J.O. Jung S. Yoo S.M. Kam T.I. Chang J. Han J. An S.S.A. Onodera T. Jung Y.K. BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid β 42. Autophagy 2013 9 12 2009 2021 10.4161/auto.26118 24145555
    [Google Scholar]
  80. Hamano T. Gendron T.F. Causevic E. Yen S.H. Lin W.L. Isidoro C. DeTure M. Ko L. Autophagic‐lysosomal perturbation enhances tau aggregation in transfectants with induced wild‐type tau expression. Eur. J. Neurosci. 2008 27 5 1119 1130 10.1111/j.1460‑9568.2008.06084.x 18294209
    [Google Scholar]
  81. Giordano S. Darley-Usmar V. Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol. 2014 2 82 90 10.1016/j.redox.2013.12.013 24494187
    [Google Scholar]
  82. 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 17 13107 13120 10.1074/jbc.M110.100420 20178983
    [Google Scholar]
  83. Steele J.W. Gandy S. Latrepirdine (Dimebon ®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 2013 9 4 617 618 10.4161/auto.23487 23380933
    [Google Scholar]
  84. Kickstein E. Krauss S. Thornhill P. Rutschow D. Zeller R. Sharkey J. Williamson R. Fuchs M. Köhler A. Glossmann H. Schneider R. Sutherland C. Schweiger S. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. USA 2010 107 50 21830 21835 10.1073/pnas.0912793107 21098287
    [Google Scholar]
  85. Tian Y. Bustos V. Flajolet M. Greengard P. A small‐molecule enhancer of autophagy decreases levels of Aβ and APP‐CTF via Atg5‐dependent autophagy pathway. FASEB J. 2011 25 6 1934 1942 10.1096/fj.10‑175158 21368103
    [Google Scholar]
  86. Forlenza O.V. de Paula V.J. Machado-Vieira R. Diniz B.S. Gattaz W.F. Does lithium prevent Alzheimer’s disease? Drugs Aging 2012 29 5 335 342 10.2165/11599180‑000000000‑00000 22500970
    [Google Scholar]
  87. Vingtdeux V. Giliberto L. Zhao H. Chandakkar P. Wu Q. Simon J.E. Janle E.M. Lobo J. Ferruzzi M.G. Davies P. Marambaud P. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J. Biol. Chem. 2010 285 12 9100 9113 10.1074/jbc.M109.060061 20080969
    [Google Scholar]
  88. Liu D. Pitta M. Jiang H. Lee J.H. Zhang G. Chen X. Kawamoto E.M. Mattson M.P. Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: Evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol. Aging 2013 34 6 1564 1580 10.1016/j.neurobiolaging.2012.11.020 23273573
    [Google Scholar]
  89. Shoji-Kawata S. Sumpter R. Leveno M. Campbell G.R. Zou Z. Kinch L. Wilkins A.D. Sun Q. Pallauf K. MacDuff D. Huerta C. Virgin H.W. Helms J.B. Eerland R. Tooze S.A. Xavier R. Lenschow D.J. Yamamoto A. King D. Lichtarge O. Grishin N.V. Spector S.A. Kaloyanova D.V. Levine B. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 2013 494 7436 201 206 10.1038/nature11866 23364696
    [Google Scholar]
  90. Ching J.K. Weihl C.C. Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy 2013 9 5 799 800 10.4161/auto.23958 23439279
    [Google Scholar]
  91. Sato S. Uchihara T. Fukuda T. Noda S. Kondo H. Saiki S. Komatsu M. Uchiyama Y. Tanaka K. Hattori N. Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice. Sci. Rep. 2018 8 1 2813 10.1038/s41598‑018‑21325‑w 29434298
    [Google Scholar]
  92. Tanik S.A. Schultheiss C.E. Volpicelli-Daley L.A. Brunden K.R. Lee V.M.Y. Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy. J. Biol. Chem. 2013 288 21 15194 15210 10.1074/jbc.M113.457408 23532841
    [Google Scholar]
  93. Hoffmann A.C. Minakaki G. Menges S. Salvi R. Savitskiy S. Kazman A. Vicente Miranda H. Mielenz D. Klucken J. Winkler J. Xiang W. Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. Sci. Rep. 2019 9 1 544 10.1038/s41598‑018‑35811‑8 30679445
    [Google Scholar]
  94. Decressac M. Mattsson B. Weikop P. Lundblad M. Jakobsson J. Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl. Acad. Sci. USA 2013 110 19 E1817 E1826 10.1073/pnas.1305623110 23610405
    [Google Scholar]
  95. Torra A. Parent A. Cuadros T. Rodríguez-Galván B. Ruiz-Bronchal E. Ballabio A. Bortolozzi A. Vila M. Bové J. Overexpression of TFEB drives a pleiotropic neurotrophic effect and prevents Parkinson’s disease-related neurodegeneration. Mol. Ther. 2018 26 6 1552 1567 10.1016/j.ymthe.2018.02.022 29628303
    [Google Scholar]
  96. García-Sanz P. Orgaz L. Bueno-Gil G. Espadas I. Rodríguez-Traver E. Kulisevsky J. Gutierrez A. Dávila J.C. González-Polo R.A. Fuentes J.M. Mir P. Vicario C. Moratalla R. N370S‐GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson’s disease. Mov. Disord. 2017 32 10 1409 1422 10.1002/mds.27119 28779532
    [Google Scholar]
  97. Yap T.L. Velayati A. Sidransky E. Lee J.C. Membrane-bound α-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol. Genet. Metab. 2013 108 1 56 64 10.1016/j.ymgme.2012.11.010 23266198
    [Google Scholar]
  98. Tong Y. Yamaguchi H. Giaime E. Boyle S. Kopan R. Kelleher R.J. Shen J. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. Proc. Natl. Acad. Sci. USA 2010 107 21 9879 9884 10.1073/pnas.1004676107 20457918
    [Google Scholar]
  99. Sánchez-Danés A. Richaud-Patin Y. Carballo-Carbajal I. Jiménez-Delgado S. Caig C. Mora S. Di Guglielmo C. Ezquerra M. Patel B. Giralt A. Canals J.M. Memo M. Alberch J. López-Barneo J. Vila M. Cuervo A.M. Tolosa E. Consiglio A. Raya A. Disease‐specific phenotypes in dopamine neurons from human iPS‐based models of genetic and sporadic Parkinson’s disease. EMBO Mol. Med. 2012 4 5 380 395 10.1002/emmm.201200215 22407749
    [Google Scholar]
  100. Wallings R. Connor-Robson N. Wade-Martins R. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Hum. Mol. Genet. 2019 28 16 2696 2710 10.1093/hmg/ddz088 31039583
    [Google Scholar]
  101. Dehay B. Ramirez A. Martinez-Vicente M. Perier C. Canron M.H. Doudnikoff E. Vital A. Vila M. Klein C. Bezard E. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl. Acad. Sci. USA 2012 109 24 9611 9616 10.1073/pnas.1112368109 22647602
    [Google Scholar]
  102. Bento C.F. Ashkenazi A. Jimenez-Sanchez M. Rubinsztein D.C. The Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat. Commun. 2016 7 1 11803 10.1038/ncomms11803 27278822
    [Google Scholar]
  103. Wang R. Tan J. Chen T. Han H. Tian R. Tan Y. Wu Y. Cui J. Chen F. Li J. Lv L. Guan X. Shang S. Lu J. Zhang Z. ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion. J. Cell Biol. 2019 218 1 267 284 10.1083/jcb.201804165 30538141
    [Google Scholar]
  104. Miura E. Hasegawa T. Konno M. Suzuki M. Sugeno N. Fujikake N. Geisler S. Tabuchi M. Oshima R. Kikuchi A. Baba T. Wada K. Nagai Y. Takeda A. Aoki M. VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease. Neurobiol. Dis. 2014 71 1 13 10.1016/j.nbd.2014.07.014 25107340
    [Google Scholar]
  105. Anderson D.G. Ferreira-Correia A. Rodrigues F.B. Aziz N.A. Carr J. Wild E.J. Margolis R.L. Krause A. Comparison of the huntington’s disease like 2 and huntington’s disease clinical phenotypes. Mov. Disord. Clin. Pract. 2019 6 4 302 311 10.1002/mdc3.12742 31061838
    [Google Scholar]
  106. Martinez-Vicente M. Talloczy Z. Wong E. Tang G. Koga H. Kaushik S. de Vries R. Arias E. Harris S. Sulzer D. Cuervo A.M. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 2010 13 5 567 576 10.1038/nn.2528 20383138
    [Google Scholar]
  107. Mealer R.G. Murray A.J. Shahani N. Subramaniam S. Snyder S.H. Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J. Biol. Chem. 2014 289 6 3547 3554 10.1074/jbc.M113.536912 24324270
    [Google Scholar]
  108. Deng H.X. Chen W. Hong S.T. Boycott K.M. Gorrie G.H. Siddique N. Yang Y. Fecto F. Shi Y. Zhai H. Jiang H. Hirano M. Rampersaud E. Jansen G.H. Donkervoort S. Bigio E.H. Brooks B.R. Ajroud K. Sufit R.L. Haines J.L. Mugnaini E. Pericak-Vance M.A. Siddique T. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011 477 7363 211 215 10.1038/nature10353 21857683
    [Google Scholar]
  109. Rudnick N.D. Griffey C.J. Guarnieri P. Gerbino V. Wang X. Piersaint J.A. Tapia J.C. Rich M.M. Maniatis T. Distinct roles for motor neuron autophagy early and late in the SOD1 G93A mouse model of ALS. Proc. Natl. Acad. Sci. USA 2017 114 39 E8294 E8303 10.1073/pnas.1704294114 28904095
    [Google Scholar]
  110. Barmada S.J. Serio A. Arjun A. Bilican B. Daub A. Ando D.M. Tsvetkov A. Pleiss M. Li X. Peisach D. Shaw C. Chandran S. Finkbeiner S. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat. Chem. Biol. 2014 10 8 677 685 10.1038/nchembio.1563 24974230
    [Google Scholar]
  111. Şentürk M. Lin G. Zuo Z. Mao D. Watson E. Mikos A.G. Bellen H.J. Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification. Nat. Cell Biol. 2019 21 3 384 396 10.1038/s41556‑019‑0281‑x 30804504
    [Google Scholar]
  112. Osaka M. Ito D. Suzuki N. Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2. Biochem. Biophys. Res. Commun. 2016 472 2 324 331 10.1016/j.bbrc.2016.02.107 26944018
    [Google Scholar]
  113. Hadano S. Mitsui S. Pan L. Otomo A. Kubo M. Sato K. Ono S. Onodera W. Abe K. Chen X. Koike M. Uchiyama Y. Aoki M. Warabi E. Yamamoto M. Ishii T. Yanagawa T. Shang H.F. Yoshii F. Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: Cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice. Hum. Mol. Genet. 2016 25 15 3321 3340 10.1093/hmg/ddw180 27439389
    [Google Scholar]
  114. Gal J. Ström 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 4 1062 1073 10.1111/j.1471‑4159.2009.06388.x 19765191
    [Google Scholar]
  115. Korac J. Schaeffer V. Kovacevic I. Clement A.M. Jungblut B. Behl C. Terzic J. Dikic I. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J. Cell Sci. 2013 126 2 580 592 10.1242/jcs.114926 23178947
    [Google Scholar]
  116. Sundaramoorthy V. Walker A.K. Tan V. Fifita J.A. Mccann E.P. Williams K.L. Blair I.P. Guillemin G.J. Farg M.A. Atkin J.D. Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis. Hum. Mol. Genet. 2015 24 13 3830 3846 10.1093/hmg/ddv126 25859013
    [Google Scholar]
  117. Cox L.E. Ferraiuolo L. Goodall E.F. Heath P.R. Higginbottom A. Mortiboys H. Hollinger H.C. Hartley J.A. Brockington A. Burness C.E. Morrison K.E. Wharton S.B. Grierson A.J. Ince P.G. Kirby J. Shaw P.J. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One 2010 5 3 9872 10.1371/journal.pone.0009872 20352044
    [Google Scholar]
  118. Lee S. Park H. Zhu P.P. Jung S.Y. Blackstone C. Chang J. Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion. Sci. Signal. 2020 13 613 eaau7500 10.1126/scisignal.aau7500 31911435
    [Google Scholar]
  119. Chang J. Lee S. Blackstone C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J. Clin. Invest. 2014 124 12 5249 5262 10.1172/JCI77598 25365221
    [Google Scholar]
  120. Vantaggiato C. Crimella C. Airoldi G. Polishchuk R. Bonato S. Brighina E. Scarlato M. Musumeci O. Toscano A. Martinuzzi A. Santorelli F.M. Ballabio A. Bresolin N. Clementi E. Bassi M.T. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain 2013 136 10 3119 3139 10.1093/brain/awt227 24030950
    [Google Scholar]
  121. Davies A.K. Itzhak D.N. Edgar J.R. Archuleta T.L. Hirst J. Jackson L.P. Robinson M.S. Borner G.H.H. AP-4 vesicles contribute to spatial control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nat. Commun. 2018 9 1 3958 10.1038/s41467‑018‑06172‑7 30262884
    [Google Scholar]
  122. Khundadze M. Ribaudo F. Hussain A. Rosentreter J. Nietzsche S. Thelen M. Winter D. Hoffmann B. Afzal M.A. Hermann T. de Heus C. Piskor E.M. Kosan C. Franzka P. von Kleist L. Stauber T. Klumperman J. Damme M. Proikas-Cezanne T. Hübner C.A. A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five. Neurobiol. Dis. 2019 127 419 431 10.1016/j.nbd.2019.03.026 30930081
    [Google Scholar]
  123. Wolfe D.M. Lee J. 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 12 1949 1961 10.1111/ejn.12169 23773064
    [Google Scholar]
  124. Malagelada C. Jin Z.H. Jackson-Lewis V. Przedborski S. Greene L.A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J. Neurosci. 2010 30 3 1166 1175 10.1523/JNEUROSCI.3944‑09.2010 20089925
    [Google Scholar]
  125. Wang C. Zhang X. Teng Z. Zhang T. Li Y. Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur. J. Pharmacol. 2014 740 312 320 10.1016/j.ejphar.2014.06.051 25041840
    [Google Scholar]
  126. Jiang T.F. Zhang Y.J. Zhou H.Y. Wang H.M. Tian L.P. Liu J. Ding J.Q. Chen S.D. Curcumin ameliorates the neurodegenerative pathology in A53T α-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J. Neuroimmune Pharmacol. 2013 8 1 356 369 10.1007/s11481‑012‑9431‑7 23325107
    [Google Scholar]
  127. DeBosch B.J. Heitmeier M.R. Mayer A.L. Higgins C.B. Crowley J.R. Kraft T.E. Chi M. Newberry E.P. Chen Z. Finck B.N. Davidson N.O. Yarasheski K.E. Hruz P.W. Moley K.H. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci. Signal. 2016 9 416 ra21 10.1126/scisignal.aac5472 26905426
    [Google Scholar]
  128. 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 7 1101 1111 10.1083/jcb.200504035 16186256
    [Google Scholar]
  129. Park H. Kang J.H. Lee S. Autophagy in neurodegenerative diseases: A hunter for aggregates. Int. J. Mol. Sci. 2020 21 9 3369 10.3390/ijms21093369 32397599
    [Google Scholar]
/content/journals/cn/10.2174/011570159X377552250627113915
Loading
/content/journals/cn/10.2174/011570159X377552250627113915
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test