title: Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease.
abstract: Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, the main process responsible for bulk autophagic degradation, have been proposed to contribute to pathogenesis in Huntington's disease (HD), a genetic neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin protein. However, the precise mechanism behind macroautophagy malfunction in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from humans with HD, we have identified a primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo in HD cells. Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen. We propose that inefficient engulfment of cytosolic components by autophagosomes is responsible for their slower turnover, functional decay and accumulation inside HD cells.
authors.affiliation: Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vicente
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Talloczy
authors.forename: Esther
authors.initials: E
authors.lastname: Wong
authors.forename: Guomei
authors.initials: G
authors.lastname: Tang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.forename: Susmita
authors.initials: S
authors.lastname: Kaushik
authors.forename: Rosa
authors.initials: R
authors.lastname: de Vries
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.forename: Spike
authors.initials: S
authors.lastname: Harris
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D010455:Peptides / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D044967:Serum / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014748:Vinca Alkaloids / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C477012:MAP1LC3A protein, human; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014748:Vinca Alkaloids; C097188:polyglutamine; D019284:Thapsigargin; C016422:eburnamonine; D020123:Sirolimus
references.citation: Hum Mol Genet. 1999 Jan;8(1):115-22
references.pmid: 9887339
references.citation: J Cell Biol. 2007 Nov 5;179(3):485-500
references.pmid: 17984323
references.citation: J Neurosci. 2001 Dec 15;21(24):9549-60
references.pmid: 11739566
references.citation: Autophagy. 2005 Apr;1(1):11-22
references.pmid: 16874045
references.citation: J Biol Chem. 2007 Feb 23;282(8):5641-52
references.pmid: 17182613
references.citation: FEBS J. 2008 Sep;275(17):4263-70
references.pmid: 18637946
references.citation: Hum Mol Genet. 2007 Nov 1;16(21):2600-15
references.pmid: 17704510
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5805-10
references.pmid: 16585521
references.citation: J Biochem. 1983 Feb;93(2):547-56
references.pmid: 6841352
references.citation: J Biol Chem. 2009 Apr 10;284(15):9796-803
references.pmid: 19218238
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:358-82
references.pmid: 19076457
references.citation: Science. 2004 Aug 27;305(5688):1292-5
references.pmid: 15333840
references.citation: Ann Neurol. 1997 Oct;42(4):604-12
references.pmid: 9382472
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20567-74
references.pmid: 19074260
references.citation: J Biol Chem. 2002 Jan 4;277(1):763-73
references.pmid: 11675395
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: J Biol Chem. 2006 May 19;281(20):14474-85
references.pmid: 16522639
references.citation: J Cell Biol. 1982 Apr;93(1):144-54
references.pmid: 7068752
references.citation: Methods Enzymol. 1990;182:203-25
references.pmid: 2156127
references.citation: Brain Pathol. 1999 Jan;9(1):147-63
references.pmid: 9989457
references.citation: Curr Protoc Mol Biol. 2005 May;Chapter 28:Unit 28.1
references.pmid: 18265366
references.citation: J Cell Biol. 2005 Oct 10;171(1):87-98
references.pmid: 16203860
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11869-74
references.pmid: 11050221
references.citation: J Neurosci. 2000 Oct 1;20(19):7268-78
references.pmid: 11007884
references.citation: Cell. 1997 Aug 8;90(3):537-48
references.pmid: 9267033
references.citation: Hum Mol Genet. 2000 Nov 22;9(19):2799-809
references.pmid: 11092756
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: Nature. 2009 Apr 30;458(7242):1131-5
references.pmid: 19339967
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3405-9
references.pmid: 16492755
references.citation: Neuroreport. 2004 Jun 7;15(8):1325-8
references.pmid: 15167559
references.citation: Methods Enzymol. 2009;453:217-49
references.pmid: 19216909
references.citation: J Cell Sci. 2008 May 15;121(Pt 10):1649-60
references.pmid: 18430781
references.citation: Hum Mol Genet. 2009 Feb 15;18(4):737-52
references.pmid: 19039036
references.citation: Nat Genet. 2004 Jun;36(6):585-95
references.pmid: 15146184
references.citation: Autophagy. 2007 May-Jun;3(3):181-206
references.pmid: 17224625
references.citation: J Neurosci. 2001 Nov 15;21(22):8772-81
references.pmid: 11698589
references.citation: Hum Mol Genet. 2002 May 1;11(9):1107-17
references.pmid: 11978769
references.citation: Cell. 2009 Apr 3;137(1):60-72
references.pmid: 19345187
references.citation: Hum Mol Genet. 2009 Nov 1;18(21):4153-70
references.pmid: 19654187
references.citation: Genes Dev. 2008 Jun 1;22(11):1427-38
references.pmid: 18519635
references.citation: Trends Genet. 2002 Apr;18(4):202-9
references.pmid: 11932021
references.citation: Hum Mol Genet. 2001 Jun 1;10(12):1243-54
references.pmid: 11406606
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: J Neurosci. 2002 Oct 15;22(20):8951-60
references.pmid: 12388602