David C Rubinsztein

Summary

Affiliation: University of Cambridge
Country: UK

Publications

  1. ncbi The roles of intracellular protein-degradation pathways in neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY
    Nature 443:780-6. 2006
  2. pmc Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease
    Benjamin R Underwood
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 19:3413-29. 2010
  3. pmc Complex inhibitory effects of nitric oxide on autophagy
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 0XY, UK
    Mol Cell 43:19-32. 2011
  4. ncbi A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 17:170-8. 2008
  5. doi Huntington's disease: from pathology and genetics to potential therapies
    Sara Imarisio
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Biochem J 412:191-209. 2008
  6. pmc Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity
    Shouqing Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, CB2 2XY, England, UK
    J Cell Biol 169:647-56. 2005
  7. pmc Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 0XY, UK
    J Cell Sci 121:1649-60. 2008
  8. ncbi Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein
    Sovan Sarkar
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 282:5641-52. 2007
  9. pmc Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D
    Kevin Moreau
    Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, England, UK
    J Cell Biol 196:483-96. 2012
  10. pmc Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease
    Claudia Rose
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 19:2144-53. 2010

Collaborators

Detail Information

Publications98

  1. ncbi The roles of intracellular protein-degradation pathways in neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY
    Nature 443:780-6. 2006
    ..However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases...
  2. pmc Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease
    Benjamin R Underwood
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 19:3413-29. 2010
    ..Thus, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties...
  3. pmc Complex inhibitory effects of nitric oxide on autophagy
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 0XY, UK
    Mol Cell 43:19-32. 2011
    ..Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition...
  4. ncbi A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 17:170-8. 2008
    ....
  5. doi Huntington's disease: from pathology and genetics to potential therapies
    Sara Imarisio
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Biochem J 412:191-209. 2008
    ..Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies...
  6. pmc Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity
    Shouqing Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, CB2 2XY, England, UK
    J Cell Biol 169:647-56. 2005
    ..These data predict that the ability of cdk5 phosphorylation to protect against htt cleavage, aggregation, and toxicity is compromised in cells expressing toxic fragments of htt...
  7. pmc Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 0XY, UK
    J Cell Sci 121:1649-60. 2008
    ..Thus, better understanding of Rab5-regulated autophagy might lead to rational therapeutic targets for HD and other protein-conformation diseases...
  8. ncbi Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein
    Sovan Sarkar
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 282:5641-52. 2007
    ....
  9. pmc Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D
    Kevin Moreau
    Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, England, UK
    J Cell Biol 196:483-96. 2012
    ..However, Arf6 may also influence autophagy by indirect effects, such as either by regulating membrane flow from other compartments or by modulating PLD activity independently of the mammalian target of rapamycin...
  10. pmc Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease
    Claudia Rose
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 19:2144-53. 2010
    ..As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions...
  11. ncbi Rapamycin pre-treatment protects against apoptosis
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Cambridge, UK
    Hum Mol Genet 15:1209-16. 2006
    ....
  12. ncbi Dyneins, autophagy, aggregation and neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 1:177-8. 2005
    ..In this Addendum, we review our findings in the contexts of autophagy and neurodegeneration and consider some of the questions raised...
  13. pmc Lysosomal positioning coordinates cellular nutrient responses
    Viktor I Korolchuk
    Department of Medical Genetics, Cambridge Institute for Medical Genetics, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    Nat Cell Biol 13:453-60. 2011
    ..Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux...
  14. ncbi Dynein mutations impair autophagic clearance of aggregate-prone proteins
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Nat Genet 37:771-6. 2005
    ....
  15. pmc Lithium induces autophagy by inhibiting inositol monophosphatase
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2XY, England, UK
    J Cell Biol 170:1101-11. 2005
    ..This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate...
  16. ncbi Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Nat Genet 36:585-95. 2004
    ..Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease...
  17. ncbi Rapamycin alleviates toxicity of different aggregate-prone proteins
    Zdenek Berger
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 15:433-42. 2006
    ..Thus, our studies suggest that the scope for rapamycin as a potential therapeutic in aggregate diseases may be much broader than HD or even polyglutamine diseases...
  18. ncbi The bacterial chaperonin GroEL requires GroES to reduce aggregation and cell death in a COS-7 cell model of Huntington's disease
    Jenny Carmichael
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Neurosci Lett 330:270-4. 2002
    ..The reduction in aggregation of mutant huntingtin by GroEL/GroES was associated with protection against polyglutamine-induced cell death...
  19. ncbi Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases
    Julie L Webb
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Int J Biochem Cell Biol 36:2541-50. 2004
    ....
  20. pmc Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection
    Maurizio Renna
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    J Clin Invest 121:3554-63. 2011
    ....
  21. ncbi Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease
    Coralie Vacher
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, UK
    Hum Mol Genet 14:3425-33. 2005
    ....
  22. doi Regulation of mammalian autophagy in physiology and pathophysiology
    Brinda Ravikumar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, United Kingdom
    Physiol Rev 90:1383-435. 2010
    ..Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions...
  23. ncbi Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin
    Andreas Wyttenbach
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 11:1137-51. 2002
    ..We propose that a poly(Q) mutation can induce ROS that directly contribute to cell death and that HSP27 is an antagonist of this process...
  24. doi Huntington's disease: degradation of mutant huntingtin by autophagy
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    FEBS J 275:4263-70. 2008
    ..We also report the growing list of new drugs/pathways that upregulate autophagy to enhance the clearance of this mutant protein, as autophagy upregulation may be a tractable strategy for the treatment of Huntington's disease...
  25. ncbi Oculopharyngeal muscular dystrophy: potential therapies for an aggregate-associated disorder
    Janet E Davies
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Int J Biochem Cell Biol 38:1457-62. 2006
    ..Indeed, administration of known anti-aggregation drugs attenuated muscle weakness in an OPMD mouse model. This suggests that anti-aggregation therapies may be beneficial in OPMD...
  26. doi Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy
    Janet E Davies
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Sci Transl Med 2:34ra40. 2010
    ..Therefore, inhibitors of transglutaminase 2 should be considered as possible therapeutics for OPMD...
  27. ncbi Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy
    Janet E Davies
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Cambridge, UK
    Hum Mol Genet 15:23-31. 2006
    ..Thus, anti-aggregation therapy may prove effective in the treatment of human OPMD...
  28. pmc Plasma membrane contributes to the formation of pre-autophagosomal structures
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Nat Cell Biol 12:747-57. 2010
    ....
  29. ncbi Decreased cAMP response element-mediated transcription: an early event in exon 1 and full-length cell models of Huntington's disease that contributes to polyglutamine pathogenesis
    Katharine L Sugars
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 279:4988-99. 2004
    ....
  30. pmc The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes
    Luca Jahreiss
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Traffic 9:574-87. 2008
    ..Indeed, although the formation of autophagosomes is completely different from any other vesicular structures, their later itinerary appears to be very similar to those of other trafficking pathways...
  31. pmc Bim inhibits autophagy by recruiting Beclin 1 to microtubules
    Shouqing Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
    Mol Cell 47:359-70. 2012
    ..Our data suggest that Bim switches locations between apoptosis-inactive/autophagy-inhibitory and apoptosis-active/autophagy-permissive sites...
  32. pmc Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy
    Fiona M Menzies
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
    Hum Mol Genet 19:4573-86. 2010
    ..Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity...
  33. ncbi Methodological considerations for assessing autophagy modulators: a study with calcium phosphate precipitates
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
    Autophagy 5:307-13. 2009
    ..Finally, the complex consequences of CPP on autophagy suggest that it is best avoided as a transfection reagent in studies aiming to analyze autophagy itself, or processes that are modulated by autophagy, like apoptosis...
  34. doi Autophagic clearance of aggregate-prone proteins associated with neurodegeneration
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Methods Enzymol 453:83-110. 2009
    ..Using these methods, we recently described several mTOR-independent autophagy-enhancing compounds that have protective effects in various models of Huntington's disease...
  35. pmc Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates
    Viktor I Korolchuk
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Mol Cell 33:517-27. 2009
    ..This will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences...
  36. ncbi 1-O-Hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol (Gln) induces cell death with more autophagosomes which is autophagy-independent
    Luca Jahreiss
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
    Autophagy 5:835-46. 2009
    ..The increased number of autophagolysosomes, however, is just a side effect of the neutralization of the lysosomal pH by Gln...
  37. pmc α-Synuclein impairs macroautophagy: implications for Parkinson's disease
    Ashley R Winslow
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK
    J Cell Biol 190:1023-37. 2010
    ..Rab1a, α-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors...
  38. ncbi Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages
    R Andres Floto
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 3:620-2. 2007
    ..These SMERs also protected against mutant huntingtin fragment toxicity in Drosophila. We have subsequently tested two of the SMERs in models of tuberculosis and both enhance the killing of mycobacteria by primary human macrophages...
  39. pmc Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases
    Maurizio Renna
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, United Kingdom
    J Biol Chem 285:11061-7. 2010
    ..In addition, we will consider some of the drugs and associated signaling pathways that can be used to induce autophagy with these therapeutic aims in mind...
  40. pmc Autophagosome precursor maturation requires homotypic fusion
    Kevin Moreau
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 20Y, UK
    Cell 146:303-17. 2011
    ....
  41. doi Small molecule enhancers of autophagy for neurodegenerative diseases
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge, UK
    Mol Biosyst 4:895-901. 2008
    ..We will discuss various autophagy-inducing small molecules that have emerged in the past few years that may be leads towards the treatment of such devastating diseases...
  42. pmc Huntingtin promotes cell survival by preventing Pak2 cleavage
    Shouqing Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    J Cell Sci 122:875-85. 2009
    ..Thus, huntingtin exerts anti-apoptotic effects by binding to Pak2, which reduces the abilities of caspase-3 and caspase-8 to cleave Pak2 and convert it into a mediator of cell death...
  43. doi Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation
    Janet E Davies
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Hum Mol Genet 17:1097-108. 2008
    ..This raises the possibility that a compromise of the anti-apoptotic function of PABPN1 might contribute to the disease mechanism of OPMD...
  44. doi Spinocerebellar ataxias caused by polyglutamine expansions: a review of therapeutic strategies
    Benjamin R Underwood
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 0XY, UK
    Cerebellum 7:215-21. 2008
    ..Finally, we review clinical trials and consider the problems of translating the increasing amount of promising laboratory data into human trials...
  45. ncbi Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 12:985-94. 2003
    ..As mTOR and Akt regulate a diversity of crucial cellular processes, our data also suggest a major new set of targets for intracellular glucose signalling...
  46. pmc The Parkinson disease protein α-synuclein inhibits autophagy
    Ashley R Winslow
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 7:429-31. 2011
    ..We discuss our mechanistic understanding of this phenomenon and also speculate how a deficiency in autophagy may contribute to a range of pleiotropic features of PD biology...
  47. ncbi p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity
    Shouqing Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 17:895-905. 2008
    ..Our data reveal a novel mechanism regulating muhtt oligomerization and toxicity and suggest that pathology may be at least partly dependent on soluble muhtt-muhtt interactions...
  48. pmc Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex
    Maurizio Renna
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB20XY, UK
    J Cell Sci 124:469-82. 2011
    ..Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system...
  49. ncbi Broadening the therapeutic scope for rapamycin treatment
    Fiona M Menzies
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 6:286-7. 2010
    ..Rapamycin, administered from the initial onset of disease signs, improves motor coordination and results in a decrease in the levels of soluble mutant ataxin-3 and protein aggregates in the brain...
  50. ncbi Huntington's disease: molecular basis of neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute of Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Expert Rev Mol Med 5:1-21. 2003
    ..In this review we consider the current status of research in the field and possible mechanisms whereby the HD mutation might result in neurodegeneration...
  51. pmc The Hedgehog signalling pathway regulates autophagy
    Maria Jimenez-Sanchez
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Nat Commun 3:1200. 2012
    ....
  52. pmc Autophagy and misfolded proteins in neurodegeneration
    Daniel J Metcalf
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Exp Neurol 238:22-8. 2012
    ..Finally, we discuss how antioxidants, which have been considered to be beneficial in neurodegenerative diseases, can block autophagy, thus potentially compromising their therapeutic potential...
  53. doi Mechanisms of autophagosome biogenesis
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Cambridge CB2 0XY, UK
    Curr Biol 22:R29-34. 2012
    ....
  54. doi Functional genomics approaches to neurodegenerative diseases
    David C Rubinsztein
    Department of Medical Genetics, Addenbrooke s Hospital, Cambridge Institute for Medical Research, Wellcome MRC Building, Hills Road, Cambridge, CB2 2XY, UK
    Mamm Genome 19:587-90. 2008
    ..In this minireview, I focus on how modifier screens in organisms from yeast to mice may be of value in helping to elucidate pathogenic pathways...
  55. pmc The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias
    Janet E Davies
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    BMC Biochem 8:S2. 2007
    ..Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com)...
  56. ncbi Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation
    Jenny Carmichael
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    J Biol Chem 277:33791-8. 2002
    ..Since LiCl can protect against polyglutamine toxicity in cell lines, it is an excellent candidate for further in vivo therapeutic trials...
  57. ncbi Transcriptional abnormalities in Huntington disease
    Katharine L Sugars
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust Medical Research Council Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Trends Genet 19:233-8. 2003
    ..Recent microarray studies also show relevant changes in gene expression profiles in HD models, providing useful information on the potential consequences of disrupted transcriptional pathways in HD...
  58. pmc Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3
    Fiona M Menzies
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK
    Brain 133:93-104. 2010
    ..However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear...
  59. ncbi Paradoxical aggregation versus oligomerisation properties of mutant and wild-type huntingtin fragments
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Exp Neurol 199:243-4. 2006
  60. ncbi Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 2:132-4. 2006
    ..In this Addendum, we review these findings, and some of the speculative possibilities they raise...
  61. ncbi Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 11:1107-17. 2002
    ..However, while poly(Q) aggregation was enhanced by lactacystin in our inducible PC12 cell model, aggregation was reduced by epoxomicin, suggesting that some other protein(s) induced by epoxomicin may regulate poly(Q) aggregation...
  62. doi Biology and trafficking of ATG9 and ATG16L1, two proteins that regulate autophagosome formation
    Eszter Zavodszky
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    FEBS Lett 587:1988-96. 2013
    ..Here we review the biology of autophagy with a focus on ATG16L1 and ATG9, and we summarise the current knowledge of their trafficking in relation to autophagic stimuli and autophagosome formation...
  63. pmc Autophagy and polyglutamine diseases
    Maria Jimenez-Sanchez
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK
    Prog Neurobiol 97:67-82. 2012
    ..We will also discuss some of the currently known mechanisms that induce autophagy, which may be beneficial for the treatment of these and other neurodegenerative disorders...
  64. pmc Cytoprotective roles for autophagy
    Kevin Moreau
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrookes Hospital, Hills Rd, Cambridge, UK
    Curr Opin Cell Biol 22:206-11. 2010
    ..These effects are pertinent to the roles of autophagy in normal human physiology, including the early neonatal period and ageing, as well as a variety of diseases, including cancer, neurodegenerative conditions and infectious diseases...
  65. doi Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems
    Viktor I Korolchuk
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    FEBS Lett 584:1393-8. 2010
    ..Here we critically review these findings and outline some outstanding issues that still await clarification...
  66. ncbi Alpha-Synuclein is degraded by both autophagy and the proteasome
    Julie L Webb
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Medical Research Council Building, Addenbrooke s Hospital, Hills Road, United Kingdom
    J Biol Chem 278:25009-13. 2003
    ..Since rapamycin, a stimulator of autophagy, increased clearance of alpha-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans...
  67. ncbi Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway
    Zdenek Berger
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    Hum Mol Genet 14:3003-11. 2005
    ....
  68. ncbi Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice
    Janet E Davies
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Nat Med 11:672-7. 2005
    ..Doxycycline may represent a safe and feasible therapeutic for this disease...
  69. ncbi Protective roles for induction of autophagy in multiple proteinopathies
    Fiona M Menzies
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Autophagy 2:224-5. 2006
    ..Second, our recent work suggests that autophagy induction may have additional cytoprotective effects by protecting cells against a range of subsequent pro-apoptotic insults...
  70. pmc Small molecules enhance autophagy and reduce toxicity in Huntington's disease models
    Sovan Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Nat Chem Biol 3:331-8. 2007
    ..Thus, we have demonstrated proof of principle for a new approach for discovery of small-molecule modulators of mammalian autophagy...
  71. ncbi Autophagy and its possible roles in nervous system diseases, damage and repair
    David C Rubinsztein
    Departments of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, UK
    Autophagy 1:11-22. 2005
    ..While many issues remain unresolved, these conditions raise the possibility that autophagy can have either deleterious or protective effects depending on the specific situation and stage in the pathological process...
  72. ncbi How does the Huntington's disease mutation damage cells?
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Cambridge, CB2 2XY, UK
    Sci Aging Knowledge Environ 2003:PE26. 2003
    ....
  73. pmc Protein-protein interaction networks in the spinocerebellar ataxias
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Genome Biol 7:229. 2006
    ....
  74. ncbi How useful are animal models of human disease?
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, CB2 2XY, Cambridge, UK
    Semin Cell Dev Biol 14:1-2. 2003
  75. ncbi Potential therapeutic applications of autophagy
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK
    Nat Rev Drug Discov 6:304-12. 2007
    ..A better understanding of autophagy is needed to allow its manipulation for therapeutic purposes, and new insights into the molecular mechanisms of autophagy are now leading to the discovery of exciting new potential drug targets...
  76. doi Loss of PINK1 function affects development and results in neurodegeneration in zebrafish
    Oleg Anichtchik
    Summit, Waterbeach, Cambridge CB25 9TN, United Kingdom
    J Neurosci 28:8199-207. 2008
    ..This provides new insights into the biology of PINK1 and a possible therapeutic avenue for further investigation...
  77. ncbi Lessons from animal models of Huntington's disease
    David C Rubinsztein
    Dept of Medical Genetics, Cambridge Institute of Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    Trends Genet 18:202-9. 2002
    ..These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens...
  78. ncbi Autophagy induction rescues toxicity mediated by proteasome inhibition
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 0XY, UK
    Neuron 54:854-6. 2007
    ..Their tantalizing results suggest that overexpression of HDAC6 may increase flux through the autophagy pathway, thereby attenuating the toxicity resulting from proteasome inhibition...
  79. ncbi Can autophagy protect against neurodegeneration caused by aggregate-prone proteins?
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Neuroreport 15:2443-5. 2004
    ..Here we discuss how the autophagy-lysosome pathway may regulate protein clearance in some of the protein conformation disorders and why this pathway may represent a possible therapeutic target in such conditions...
  80. ncbi Role of autophagy in the clearance of mutant huntingtin: a step towards therapy?
    Brinda Ravikumar
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
    Mol Aspects Med 27:520-7. 2006
    ..Interestingly, the aggregates formed by mutant huntingtin sequester and inactivate the mammalian target of rapamycin (mTOR), a key negative regulator of autophagy. This results in induction of autophagy in cells with these aggregates...
  81. ncbi Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy
    Yi Ping Bao
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 277:12263-9. 2002
    ....
  82. pmc Novel targets for Huntington's disease in an mTOR-independent autophagy pathway
    Andrea Williams
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Nat Chem Biol 4:295-305. 2008
    ..Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins...
  83. pmc Autophagy in neurodegeneration and development
    Ashley R Winslow
    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Biochim Biophys Acta 1782:723-9. 2008
    ..We will also discuss the importance of autophagy in early stages of development and its possible contribution as a secondary disease mechanism in forms of fronto-temporal dementias, motor neuron disease, and lysosomal storage disorders...
  84. ncbi Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease
    Yonghong Li
    Celera, 1401 Harbor Bay Parkway, Alameda, CA 94502, USA
    Hum Mol Genet 17:759-67. 2008
    ..These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD...
  85. ncbi Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin
    Hui Yang
    Medical Biotechnology Center, University of Maryland Biotechnology Institute, 725 W Lombard Street, Baltimore, MD 21201, USA
    Exp Cell Res 313:538-50. 2007
    ..These results suggest that Hrd1 is a novel htt-interacting protein that can target pathogenic httN for degradation and is able to protect cells against httN-induced cell death...
  86. ncbi Lysosomal storage diseases as disorders of autophagy
    Carmine Settembre
    Telethon Institute of Genetics and Medicine TIGEM, Naples, Italy
    Autophagy 4:113-4. 2008
    ..These findings suggest that neurodegeneration in LSDs may share some mechanisms with late-onset neurodegenerative disorders in which the accumulation of protein aggregates is a prominent feature...
  87. ncbi Modulation of polyglutamine-induced cell death by genes identified by expression profiling
    Hiroko Kita
    Taisho Laboratory of Functional Genomics, Nara Institute of Science and Technology, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 8916 5 Takayama, Ikoma, Nara, 630 0101, Japan
    Hum Mol Genet 11:2279-87. 2002
    ..The efficient recovery of functionally relevant genes supports the utility of gene expression profiling for discovering pathways related to pathogenesis, and the importance of analyzing molecular events in the early stages of disease...
  88. doi Clearance of mutant aggregate-prone proteins by autophagy
    Brinda Ravikumar
    Department of Medical Genetics, University of Cambridge, Cambridge, UK
    Methods Mol Biol 445:195-211. 2008
    ..Inhibition of autophagy has opposite effects. Thus, the autophagic pathway may represent a possible therapeutic target in the treatment of certain protein conformation disorders...
  89. ncbi Does bafilomycin A1 block the fusion of autophagosomes with lysosomes?
    Daniel J Klionsky
    Autophagy 4:849-950. 2008
    ..However, data from one of our labs noted an apparently different result in a relatively recent manuscript. Therefore, we decided to look into this more carefully...
  90. ncbi Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications
    Andrea Williams
    Department of Medical Genetics Cambridge Institute for Medical Research Addenbrooke s Hospital, Cambridge CB2 2XY United Kingdom
    Curr Top Dev Biol 76:89-101. 2006
    ....
  91. pmc Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function
    Anat Yanai
    Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
    Nat Neurosci 9:824-31. 2006
    ..These results suggest that the expansion of the polyglutamine tract in htt results in decreased palmitoylation, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity...
  92. ncbi A block of autophagy in lysosomal storage disorders
    Carmine Settembre
    Telethon Institute of Genetics and Medicine TIGEM, Naples, Italy
    Hum Mol Genet 17:119-29. 2008
    ..These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases...
  93. pmc Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease
    Robert J Ferrante
    Geriatric Research and Education and Clinical Center, Veterans Administration Medical Center, Bedford, MA, USA
    J Neurosci 24:10335-42. 2004
    ..Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD...
  94. ncbi Mutant huntingtin represses CBP, but not p300, by binding and protein degradation
    Shu yan Cong
    CBG Center of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands, and Department of Neurology, The Second Affiliated Hospital of China Medical University, Shenyang, China
    Mol Cell Neurosci 30:560-71. 2005
    ..In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyl transferases may affect chromatin structure and transcription and thus contribute to neurodegeneration...
  95. ncbi Mutant huntingtin represses CBP, but not p300, by binding and protein degradation
    Shu yan Cong
    CBG Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
    Mol Cell Neurosci 30:12-23. 2005
    ..In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyltransferases may affect chromatin structure and transcription and thus contribute to neurodegeneration...
  96. ncbi Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein
    Wei Li
    Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 2XY, United Kingdom
    J Biol Chem 281:15916-22. 2006
    ..Here we report the expression and preliminary characterization of recombinant full-length wild-type human htt. Our results support a model of htt composed entirely of HEAT repeats that stack to form an elongated superhelix...
  97. ncbi Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
    Benjamin R Underwood
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, UK
    Brain 129:877-86. 2006
    ....
  98. ncbi Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion
    Zdenek Berger
    Department of Medical Genetics, University of Cambridge, Cambridge, UK
    Hum Mol Genet 15:453-65. 2006
    ..Thus, overexpression of an aggregate-prone protein without any normal functions can result in both pathogenic and protective effects in cell culture and in vivo...