0
Neurological Review |

Beclin 1 Complex in Autophagy and Alzheimer Disease FREE

Philipp A. Jaeger, Dipl-Biochem; Tony Wyss-Coray, PhD
[+] Author Affiliations

Author Affiliations: Freie Universität Berlin, Institut für Chemie und Biochemie, Berlin, Germany (Mr Jaeger); and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford (Mr Jaeger and Dr Wyss-Coray) and Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto (Dr Wyss-Coray), California.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2010;67(10):1181-1184. doi:10.1001/archneurol.2010.258.
Text Size: A A A
Published online

Beclin 1 is a protein involved in the regulation of autophagy and has been shown to be reduced in patients with Alzheimer disease. This review summarizes the current research data that link disturbances in autophagy, a cellular degradation and maintenance pathway, to the development of Alzheimer disease and related neurodegenerative diseases. It also provides a brief overview of the existing pharmacological interventions available to modulate autophagy activity in mammalian cells.

Figures in this Article

Alzheimer disease (AD) is the most common form of dementia. It is a slowly progressive, neurodegenerative disorder that causes memory impairments and other cognitive dysfunctions. While numerous genetic risk factors for the development of AD have been identified over the past decades, our understanding of the underlying pathogenesis is still incomplete. No cure is available to date and current treatment strategies are mostly symptomatic. On the neuropathological level, the disease is identified by the presence of intracellular protein deposits (hyperphosphorylated tau protein in neurofibrillary tangles), extracellular aggregates (β-amyloid [Aβ] protein in amyloid plaques), and widespread brain atrophy.1 The Aβ protein, a small fragment cleaved off the amyloid precursor protein (APP), has received particular attention as a potential culprit. It exists in monomeric, oligomeric, and fibrillar form and has been implicated as a neurotoxic agent inside as well as outside the cell.2,3 More recently, other cleavage products of APP have been identified as possible players in AD pathology as well.4 Because APP is a transmembrane protein and many cleavage steps require the presence of specific proteolytic assemblies (secretases, proteases) and proper local pH value, the intracellular trafficking of APP through the membranous compartments could determine the production of APP cleavage products. This idea is supported by data showing that sortilin-related receptor mutations are genetically linked to AD and the resulting loss of endosomal sorting causes early AD pathology in mice.5,6 Now autophagy, another major vesicular trafficking pathway, has received increased attention in the AD research field.

Autophagy (from Greek for “self-eating”) is a cellular process that allows degradation of large intracellular components and recycling of valuable anabolic resources (amino acids, lipids, sugars, etc). Different types of autophagy exist, but this review focuses on macroautophagy, the most extensively studied form of autophagy in the context of neurodegeneration. While the process had first been described in yeast, the last decade saw a dramatic increase of our understanding of the underlying molecular machinery in mammalian cells.7 In short, a double membrane–bound vesicle (autophagosome) forms in the cytosol and sequesters cellular debris such as large protein complexes, damaged mitochondria, pathogens, or bulk cytosol (Figure 1). In this way, autophagy can degrade cargo that is otherwise too large to be degraded by proteases or inserted into the proteasome. The source of the membrane used for autophagosome formation has been subject to an ongoing debate as either it could be synthesized locally as the nascent autophagosome grows or it could be derived from other membranous compartments like the endoplasmic reticulum through budding and fusion. A recent, elegant study using electron microscopy suggests that, at least in mammalian cells, autophagosome membranes can be derived from an endoplasmic reticulum subdomain through the formation of a spherical, cradlelike structure.8 While autophagy initially appeared to be a bulk degradation pathway, it is now clear that substrate specificity exists, especially for ubiquitinated or acetylated protein aggregates.9,10 Autophagy is a cellular stress response that is activated through a number of pathways,7 and the mammalian target of rapamycin (mTOR) signaling cascade integrates many autophagy-related stimuli such as starvation, hypoxia, growth factors, and infections11 (Figure 1). After cargo sequestration, autophagosomes have to be transported to the perinuclear cytosol and fuse with endosomes and lysosomes for successful content degradation.12,13 Disruption of autophagosomal-endosomal-lysosomal trafficking can cause major changes in cellular vesicle turnover. Being a central metabolic pathway, autophagy plays an important role in a variety of human diseases, in cellular homeostasis, and in immunity, in both the central nervous system and other tissues.1416 Accordingly, the latest research suggests that modulating levels of autophagy has beneficial effects on general cellular health and ameliorates the effects of aging in several experimental settings.1720

Place holder to copy figure label and caption
Figure 1.

Autophagy in mammalian cells. Autophagy can be triggered through a variety of upstream signaling events such as starvation, insulin, growth factors, hypoxia, or pathogens. Many of these events converge in an inhibition of mammalian target of rapamycin (mTOR) activity, which in turn initiates autophagy. Numerous autophagy-related proteins participate in the initiation and formation of autophagosomes and in cargo recognition (see references for details). The complete autophagosome is then transported to fuse with lysosomes, and degradation of the content releases valuable anabolic compounds. PI3K indicates phosphatidylinositol 3-kinase.

Graphic Jump Location

The creation of autophagy-specific knockout mice in 2006 and the observation of their neurodegenerative phenotype brought autophagy to the attention of the broader neuroscientific community.21,22 The accumulation of autophagosomes and nondegraded material in neurons of brains in patients with AD and the presence of APP-processing secretases in autophagosomes had already indicated that autophagy participates in the turnover of APP and its metabolites and that it might be deregulated in AD.2325 Additionally, changes in autophagy and endosomal sorting-related messenger RNAs had been reported in brain tissues of patients with AD.26 A study from our laboratory then identified Beclin 1, a protein involved in the initiation and execution of autophagy, to be reduced in AD brain tissue, linking the disease to an autophagy defect (Figure 2A).27 Accordingly, APP-transgenic mice with a heterozygous deletion of Beclin 1 have an increase in Aβ plaque deposition, neuronal loss, and the accumulation of abnormal lysosomes containing electron-dense material.27 These findings indicate that autophagy plays a central role in APP transport and metabolism, a hypothesis that is further supported by new cell culture data from our laboratory: APP and APP metabolites are degraded via the autophagy pathway, and Beclin 1 reduction increases APP, APP C-terminal fragment, and Aβ accumulation in cell culture.28 Interestingly, APP overexpression, both in cells and in mice, causes no detectable change in Beclin 1 levels.27,28 This suggests that disturbances in autophagy precede the pathological disruption of APP processing. Beclin 1 had initially been identified as a tumor suppressor gene29 and is now at the center of research aiming to understand the complex molecular events surrounding autophagy initiation and execution. A series of landmark studies published in the last 3 years showed that Beclin 1 is at the core of a large protein complex that regulates multiple aspects of autophagy, depending on its subunit composition (Figure 2B).3036 The question is, to what extent is autophagy involved in the development or prevention of neurotoxic events, and can modulating autophagy cause or rescue neurodegeneration? Autophagy appears impaired in presenilin 1/APP mice and contributes to neuronal apoptosis,24,37 while it is constitutively active in healthy neurons.38 In addition, Aβ1-42 has been reported to directly impair the autophagosomal-lysosomal system in flies,39 and Aβ oligomers interfere with mTOR signaling.40 On the other hand, activation of autophagy or overexpression of Beclin 1 can prevent neuronal cell death and promote clearance of toxic protein aggregates.4143 These data suggest a model where basal autophagy plays an important role in neuronal protein housekeeping and vesicular turnover. Disruption of autophagy would lead to an accumulation of abnormal subcellular vesicles (endosomes, lysosomes, multivesicular bodies, autophagosomes), which are part of the native APP trafficking system and present the right microenvironment to produce potentially toxic APP metabolites. Increasing levels of these toxic species, including Aβ, could then contribute further to an escalating disruption of the autophagosomal system and ultimately to cell death. A rescue of autophagy levels or a mild overactivation appears to have beneficial effects, while extreme autophagy activation can lead to cell death by itself.

Place holder to copy figure label and caption
Figure 2.

The role of Beclin 1 in autophagy and Alzheimer disease (AD). A, Beclin 1 is reduced in human AD brains, at both the messenger RNA and protein levels. Accumulated autophagosomes indicate stalled autophagosomal degradation. β-Amyloid (Aβ) is produced and accumulates in amyloid plaques. Beclin 1–deficient transgenic mice expressing human amyloid precursor protein (hAPP) exhibit disturbances in their autophagosomal-lysosomal degradation and have increased amyloid plaque load. Inhibition of autophagy in hAPP-expressing cells leads to an accumulation of APP and its metabolites, while autophagy activation can reduce the levels of APP and its metabolic products. CTF indicates C-terminal fragment. B, Beclin 1 has multiple binding partners, and the composition of proteins in the Beclin 1 complex appears to determine its function. Reduced availability of Beclin 1 may cause a destabilization of the complex and could impair autophagy on multiple levels.

Graphic Jump Location

Autophagy is a major pathway of cellular homeostasis. It is regulated by a variety of important signaling cascades, and pharmacological intervention to alter autophagy levels without disrupting other main pathways may prove difficult. However, a number of studies have shown that it is possible to screen for autophagy-inducing drugs using simple cell or animal model systems of neurodegeneration (Table). Current research on the precise role of Beclin 1 and other autophagy-initiating and autophagy-modulating protein complexes will hopefully allow us to develop better drugs to fine-tune autophagy activity depending on the specific disease settings. Surprising off-target effects of established drugs for cancer treatment should be evaluated for their usefulness in autophagy modulation because many cancer and autophagy pathways overlap. Also, aging is the major risk factor for AD, and enhancing autophagy has been shown to ameliorate some age-related phenotypes and promote longevity. Thus, progress in our understanding of the role of autophagy in neurodegeneration may yield valuable insight in a multitude of geriatric conditions.

Table Graphic Jump LocationTable. Selection of Drugs With Autophagy-Inducing Effects in Cell Culture or Animal Models

Correspondence: Tony Wyss-Coray, PhD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5235 (twc@stanford.edu).

Accepted for Publication: February 9, 2010.

Author Contributions:Study concept and design: Jaeger and Wyss-Coray. Drafting of the manuscript: Jaeger. Critical revision of the manuscript for important intellectual content: Wyss-Coray. Study supervision: Wyss-Coray.

Financial Disclosure: None reported.

The article was corrected online for typographical errors on Oct 11,2010.

Blennow  Kde Leon  MJZetterberg  H Alzheimer's disease. Lancet 2006;368 (9533) 387- 403
PubMed
Haass  CSelkoe  DJ Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 2007;8 (2) 101- 112
PubMed
LaFerla  FMGreen  KNOddo  S Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 2007;8 (7) 499- 509
PubMed
Kim  DTsai  L-H Bridging physiology and pathology in AD. Cell 2009;137 (6) 997- 1000
PubMed
Dodson  SEAndersen  OMKarmali  V  et al.  Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. J Neurosci 2008;28 (48) 12877- 12886
PubMed
Rogaeva  EMeng  YLee  JH  et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39 (2) 168- 177
PubMed
He  CKlionsky  DJ Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;4367- 93
PubMed
Hayashi-Nishino  MFujita  NNoda  TYamaguchi  AYoshimori  TYamamoto  A A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009;11 (12) 1433- 1437
PubMed
Kirkin  V McEwan  DGNovak  IDikic  I A role for ubiquitin in selective autophagy. Mol Cell 2009;34 (3) 259- 269
PubMed
Jeong  HThen  FMelia  TJ  Jr  et al.  Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009;137 (1) 60- 72
PubMed
Corradetti  MNGuan  KL Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 2006;25 (48) 6347- 6360
PubMed
Ravikumar  BAcevedo-Arozena  AImarisio  S  et al.  Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 2005;37 (7) 771- 776
PubMed
Kimura  SNoda  TYoshimori  T Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct Funct 2008;33 (1) 109- 122
PubMed
Levine  BKroemer  G Autophagy in the pathogenesis of disease. Cell 2008;132 (1) 27- 42
PubMed
Jaeger  PAWyss-Coray  T All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009;416
PubMed
Virgin  HWLevine  B Autophagy genes in immunity. Nat Immunol 2009;10 (5) 461- 470
PubMed
Eisenberg  TKnauer  HSchauer  A  et al.  Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009;11 (11) 1305- 1314
PubMed
Halaschek-Wiener  JAmirabbasi-Beik  MMonfared  N  et al.  Genetic variation in healthy oldest-old. PLoS One 2009;4 (8) e6641
PubMed
Harrison  DEStrong  RSharp  ZD  et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460 (7253) 392- 395
PubMed
Zhang  CCuervo  AM Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008;14 (9) 959- 965
PubMed
Hara  TNakamura  KMatsui  M  et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441 (7095) 885- 889
PubMed
Komatsu  MWaguri  SChiba  T  et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441 (7095) 880- 884
PubMed
Nixon  RAWegiel  JKumar  A  et al.  Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005;64 (2) 113- 122
PubMed
Yu  WHCuervo  AMKumar  A  et al.  Macroautophagy: a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 2005;171 (1) 87- 98
PubMed
Yu  WHKumar  APeterhoff  C  et al.  Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol 2004;36 (12) 2531- 2540
PubMed
Small  SAKent  KPierce  A  et al.  Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol 2005;58 (6) 909- 919
PubMed
Pickford  FMasliah  EBritschgi  M  et al.  The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008;118 (6) 2190- 2199
PubMed
Jaeger  PAPickford  FSun  CHLucin  KMMasliah  EWyss-Coray  T Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One 2010;5 (6) e11102
PubMed10.1371/journal.pone.0011102
Liang  XHJackson  SSeaman  M  et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402 (6762) 672- 676
PubMed
Takahashi  YCoppola  DMatsushita  N  et al.  Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007;9 (10) 1142- 1151
PubMed
Itakura  EKishi  CInoue  KMizushima  N Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008;19 (12) 5360- 5372
PubMed
Matsunaga  KSaitoh  TTabata  K  et al.  Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009;11 (4) 385- 396
PubMed
Zhong  YWang  QJLi  X  et al.  Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 2009;11 (4) 468- 476
PubMed
Fimia  GMStoykova  ARomagnoli  A  et al.  Ambra1 regulates autophagy and development of the nervous system. Nature 2007;447 (7148) 1121- 1125
PubMed
Sun  QFan  WChen  KDing  XChen  SZhong  Q Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 2008;105 (49) 19211- 19216
PubMed
He  CLevine  B The Beclin 1 interactome. Curr Opin Cell Biol 2010;22 (2) 140- 149
PubMed
Yang  D-SKumar  AStavrides  P  et al.  Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease. Am J Pathol 2008;173 (3) 665- 681
PubMed
Boland  BKumar  ALee  S  et al.  Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci 2008;28 (27) 6926- 6937
PubMed
Ling  DSong  H-JGarza  DNeufeld  TPSalvaterra  PM Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in DrosophilaPLoS One 2009;4 (1) e4201
PubMed
Bhaskar  KMiller  MChludzinski  AHerrup  KZagorski  MLamb  BT The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener 2009;414
PubMed
Hung  SYHuang  WPLiou  HCFu  WM Autophagy protects neuron from Abeta-induced cytotoxicity. Autophagy 2009;5 (4) 502- 510
PubMed
Spencer  BPotkar  RTrejo  M  et al.  Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 2009;29 (43) 13578- 13588
PubMed
Wang  TLao  UEdgar  BA TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 2009;186 (5) 703- 711
PubMed
Rubinsztein  DCGestwicki  JEMurphy  LOKlionsky  DJ Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007;6 (4) 304- 312
PubMed
Menzies  FMHuebener  JRenna  MBonin  MRiess  ORubinsztein  DC Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 2010;133 (pt 1) 93- 104
PubMed
Balgi  ADFonseca  BDDonohue  E  et al.  Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 2009;4 (9) e7124
PubMed
Sarkar  SPerlstein  EOImarisio  S  et al.  Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol 2007;3 (6) 331- 338
PubMed
Zhang  LYu  JPan  H  et al.  Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A 2007;104 (48) 19023- 19028
PubMed
Sarkar  SFloto  RABerger  Z  et al.  Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005;170 (7) 1101- 1111
PubMed
Sarkar  SKrishna  GImarisio  SSaiki  SO’Kane  CJRubinsztein  DC A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 2008;17 (2) 170- 178
PubMed
Fornai  FLongone  PCafaro  L  et al.  Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008;105 (6) 2052- 2057
PubMed
Tanaka  MMachida  YNiu  S  et al.  Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004;10 (2) 148- 154
PubMed
Sarkar  SDavies  JEHuang  ZTunnacliffe  ARubinsztein  DC Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007;282 (8) 5641- 5652
PubMed
Williams  ASarkar  SCuddon  P  et al.  Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 2008;4 (5) 295- 305
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Autophagy in mammalian cells. Autophagy can be triggered through a variety of upstream signaling events such as starvation, insulin, growth factors, hypoxia, or pathogens. Many of these events converge in an inhibition of mammalian target of rapamycin (mTOR) activity, which in turn initiates autophagy. Numerous autophagy-related proteins participate in the initiation and formation of autophagosomes and in cargo recognition (see references for details). The complete autophagosome is then transported to fuse with lysosomes, and degradation of the content releases valuable anabolic compounds. PI3K indicates phosphatidylinositol 3-kinase.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The role of Beclin 1 in autophagy and Alzheimer disease (AD). A, Beclin 1 is reduced in human AD brains, at both the messenger RNA and protein levels. Accumulated autophagosomes indicate stalled autophagosomal degradation. β-Amyloid (Aβ) is produced and accumulates in amyloid plaques. Beclin 1–deficient transgenic mice expressing human amyloid precursor protein (hAPP) exhibit disturbances in their autophagosomal-lysosomal degradation and have increased amyloid plaque load. Inhibition of autophagy in hAPP-expressing cells leads to an accumulation of APP and its metabolites, while autophagy activation can reduce the levels of APP and its metabolic products. CTF indicates C-terminal fragment. B, Beclin 1 has multiple binding partners, and the composition of proteins in the Beclin 1 complex appears to determine its function. Reduced availability of Beclin 1 may cause a destabilization of the complex and could impair autophagy on multiple levels.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Selection of Drugs With Autophagy-Inducing Effects in Cell Culture or Animal Models

References

Blennow  Kde Leon  MJZetterberg  H Alzheimer's disease. Lancet 2006;368 (9533) 387- 403
PubMed
Haass  CSelkoe  DJ Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 2007;8 (2) 101- 112
PubMed
LaFerla  FMGreen  KNOddo  S Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 2007;8 (7) 499- 509
PubMed
Kim  DTsai  L-H Bridging physiology and pathology in AD. Cell 2009;137 (6) 997- 1000
PubMed
Dodson  SEAndersen  OMKarmali  V  et al.  Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. J Neurosci 2008;28 (48) 12877- 12886
PubMed
Rogaeva  EMeng  YLee  JH  et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39 (2) 168- 177
PubMed
He  CKlionsky  DJ Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;4367- 93
PubMed
Hayashi-Nishino  MFujita  NNoda  TYamaguchi  AYoshimori  TYamamoto  A A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009;11 (12) 1433- 1437
PubMed
Kirkin  V McEwan  DGNovak  IDikic  I A role for ubiquitin in selective autophagy. Mol Cell 2009;34 (3) 259- 269
PubMed
Jeong  HThen  FMelia  TJ  Jr  et al.  Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009;137 (1) 60- 72
PubMed
Corradetti  MNGuan  KL Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 2006;25 (48) 6347- 6360
PubMed
Ravikumar  BAcevedo-Arozena  AImarisio  S  et al.  Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 2005;37 (7) 771- 776
PubMed
Kimura  SNoda  TYoshimori  T Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct Funct 2008;33 (1) 109- 122
PubMed
Levine  BKroemer  G Autophagy in the pathogenesis of disease. Cell 2008;132 (1) 27- 42
PubMed
Jaeger  PAWyss-Coray  T All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009;416
PubMed
Virgin  HWLevine  B Autophagy genes in immunity. Nat Immunol 2009;10 (5) 461- 470
PubMed
Eisenberg  TKnauer  HSchauer  A  et al.  Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009;11 (11) 1305- 1314
PubMed
Halaschek-Wiener  JAmirabbasi-Beik  MMonfared  N  et al.  Genetic variation in healthy oldest-old. PLoS One 2009;4 (8) e6641
PubMed
Harrison  DEStrong  RSharp  ZD  et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460 (7253) 392- 395
PubMed
Zhang  CCuervo  AM Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008;14 (9) 959- 965
PubMed
Hara  TNakamura  KMatsui  M  et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441 (7095) 885- 889
PubMed
Komatsu  MWaguri  SChiba  T  et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441 (7095) 880- 884
PubMed
Nixon  RAWegiel  JKumar  A  et al.  Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005;64 (2) 113- 122
PubMed
Yu  WHCuervo  AMKumar  A  et al.  Macroautophagy: a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 2005;171 (1) 87- 98
PubMed
Yu  WHKumar  APeterhoff  C  et al.  Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol 2004;36 (12) 2531- 2540
PubMed
Small  SAKent  KPierce  A  et al.  Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol 2005;58 (6) 909- 919
PubMed
Pickford  FMasliah  EBritschgi  M  et al.  The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008;118 (6) 2190- 2199
PubMed
Jaeger  PAPickford  FSun  CHLucin  KMMasliah  EWyss-Coray  T Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One 2010;5 (6) e11102
PubMed10.1371/journal.pone.0011102
Liang  XHJackson  SSeaman  M  et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402 (6762) 672- 676
PubMed
Takahashi  YCoppola  DMatsushita  N  et al.  Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007;9 (10) 1142- 1151
PubMed
Itakura  EKishi  CInoue  KMizushima  N Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008;19 (12) 5360- 5372
PubMed
Matsunaga  KSaitoh  TTabata  K  et al.  Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009;11 (4) 385- 396
PubMed
Zhong  YWang  QJLi  X  et al.  Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 2009;11 (4) 468- 476
PubMed
Fimia  GMStoykova  ARomagnoli  A  et al.  Ambra1 regulates autophagy and development of the nervous system. Nature 2007;447 (7148) 1121- 1125
PubMed
Sun  QFan  WChen  KDing  XChen  SZhong  Q Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 2008;105 (49) 19211- 19216
PubMed
He  CLevine  B The Beclin 1 interactome. Curr Opin Cell Biol 2010;22 (2) 140- 149
PubMed
Yang  D-SKumar  AStavrides  P  et al.  Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease. Am J Pathol 2008;173 (3) 665- 681
PubMed
Boland  BKumar  ALee  S  et al.  Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci 2008;28 (27) 6926- 6937
PubMed
Ling  DSong  H-JGarza  DNeufeld  TPSalvaterra  PM Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in DrosophilaPLoS One 2009;4 (1) e4201
PubMed
Bhaskar  KMiller  MChludzinski  AHerrup  KZagorski  MLamb  BT The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener 2009;414
PubMed
Hung  SYHuang  WPLiou  HCFu  WM Autophagy protects neuron from Abeta-induced cytotoxicity. Autophagy 2009;5 (4) 502- 510
PubMed
Spencer  BPotkar  RTrejo  M  et al.  Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 2009;29 (43) 13578- 13588
PubMed
Wang  TLao  UEdgar  BA TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 2009;186 (5) 703- 711
PubMed
Rubinsztein  DCGestwicki  JEMurphy  LOKlionsky  DJ Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007;6 (4) 304- 312
PubMed
Menzies  FMHuebener  JRenna  MBonin  MRiess  ORubinsztein  DC Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 2010;133 (pt 1) 93- 104
PubMed
Balgi  ADFonseca  BDDonohue  E  et al.  Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 2009;4 (9) e7124
PubMed
Sarkar  SPerlstein  EOImarisio  S  et al.  Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol 2007;3 (6) 331- 338
PubMed
Zhang  LYu  JPan  H  et al.  Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A 2007;104 (48) 19023- 19028
PubMed
Sarkar  SFloto  RABerger  Z  et al.  Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005;170 (7) 1101- 1111
PubMed
Sarkar  SKrishna  GImarisio  SSaiki  SO’Kane  CJRubinsztein  DC A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 2008;17 (2) 170- 178
PubMed
Fornai  FLongone  PCafaro  L  et al.  Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008;105 (6) 2052- 2057
PubMed
Tanaka  MMachida  YNiu  S  et al.  Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004;10 (2) 148- 154
PubMed
Sarkar  SDavies  JEHuang  ZTunnacliffe  ARubinsztein  DC Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007;282 (8) 5641- 5652
PubMed
Williams  ASarkar  SCuddon  P  et al.  Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 2008;4 (5) 295- 305
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario