D C Rubinsztein

Summary

Affiliation: University of Cambridge
Country: UK

Publications

  1. 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
  2. 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
  3. pmc Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages
    D C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    Philos Trans R Soc Lond B Biol Sci 354:1095-9. 1999
  4. ncbi Apo E genotypes and risk of dementia in Down syndrome
    D C Rubinsztein
    Department of Medical Genetics, Addenbrooke s Hospital, Cambridge, UK
    Am J Med Genet 88:344-7. 1999
  5. 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
  6. 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
  7. 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
  8. 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
  9. pmc Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease
    A E Taylor
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    J Med Genet 38:232-3. 2001
  10. ncbi Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease
    A Wyttenbach
    Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 10:1829-45. 2001

Detail Information

Publications89

  1. 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...
  2. 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...
  3. pmc Microsatellite and trinucleotide-repeat evolution: evidence for mutational bias and different rates of evolution in different lineages
    D C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    Philos Trans R Soc Lond B Biol Sci 354:1095-9. 1999
    ..In addition, our experiments suggest that the rates of expansion of such sequences differ in related species...
  4. ncbi Apo E genotypes and risk of dementia in Down syndrome
    D C Rubinsztein
    Department of Medical Genetics, Addenbrooke s Hospital, Cambridge, UK
    Am J Med Genet 88:344-7. 1999
    ..37 (95% CI 0.14-0. 96)). Thus, apo E genotypes are associated with similar risk effects in Down syndrome dementia and late-onset Alzheimer's disease...
  5. 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
  6. 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
    ....
  7. 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...
  8. 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...
  9. pmc Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease
    A E Taylor
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    J Med Genet 38:232-3. 2001
    ..Samples were diagnosed predominantly by clinical rather than pathological criteria. We have sought to replicate this finding in a series of necropsy confirmed, late onset AD cases and non-demented controls...
  10. ncbi Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease
    A Wyttenbach
    Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK
    Hum Mol Genet 10:1829-45. 2001
    ..Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin...
  11. pmc A molecular investigation of true dominance in Huntington's disease
    Y Narain
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    J Med Genet 36:739-46. 1999
    ..Our experiments also provide a model, which may explain the different repeat size ranges seen in patients and healthy controls for the different polyglutamine diseases...
  12. pmc A locus for autosomal dominant "pure" hereditary spastic paraplegia maps to chromosome 19q13
    E Reid
    Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
    Am J Hum Genet 66:728-32. 2000
    ..Haplotype construction and analysis of recombination events narrowed the SPG12 locus to a 16.1-cM region between markers D19S868 and D19S902...
  13. ncbi No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders
    R A Furlong
    Department of Medical Genetics, University of Cambridge, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, United Kingdom
    Am J Med Genet 96:733-5. 2000
    ..These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:733-735, 2000...
  14. pmc APOE and ACE polymorphisms and dementia risk in the older population over prolonged follow-up: 10 years of incidence in the MRC CFA Study
    H A D Keage
    Department of Public Health and Primary Care, University of Cambridge, UK
    Age Ageing 39:104-11. 2010
    ..We concentrate on incident dementia risk over 10 years...
  15. pmc Alpha-synuclein overexpression promotes aggregation of mutant huntingtin
    R A Furlong
    Department of Medical Genetics, Cambridge University, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, U K
    Biochem J 346:577-81. 2000
    ..However, alpha-synuclein does not form aggregates by itself, nor does it appear in huntingtin inclusions in vitro...
  16. ncbi Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes
    A Taylor
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Am J Med Genet 105:761-4. 2001
    ..Thus, these polymorphisms are unlikely to be associated with AD risk...
  17. ncbi The molecular biology of Huntington's disease
    L W Ho
    Department of Medical Genetics, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute of Medical Research, Addenbrooke's Hospital
    Psychol Med 31:3-14. 2001
    ..Further knowledge in these areas will inspire the development of novel therapeutic strategies...
  18. ncbi Psychiatric symptoms and CAG repeats in neurologically asymptomatic Huntington's disease gene carriers
    G E Berrios
    Department of Psychiatry, University of Cambridge, Addenbrookes Hospital (Box 189, Hills Road, CB2-2QQ, Cambridge, UK
    Psychiatry Res 102:217-25. 2001
    ..Scores for irritability and cognitive failures were high in the sample. There was no correlation between any psychiatric variable and CAG repeats. Possible explanations for this lack of correlations are discussed...
  19. pmc Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease
    L W Ho
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms of Disease, Cambridge Institute for Medical Research, Wellcome MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY, UK
    J Med Genet 38:450-2. 2001
    ....
  20. doi Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies
    S Sarkar
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0XY, UK
    Cell Death Differ 16:46-56. 2009
    ..In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions...
  21. ncbi Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis
    D C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Dement Geriatr Cogn Disord 10:199-209. 1999
    ..We estimate that 60% (95% CI 48-68%) of AD cases over the age of 65 years and 92% of cases below the age of 65 would be attributable to apo E and that apo E probably accounts for less than 50% of the familial aggregation of the disease...
  22. pmc Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors
    M Futter
    CIMR, Medical Genetics, Wellcome Trust MRC Building, Addenbrooke s Hospital, Cambridge, UK
    J Med Genet 46:438-46. 2009
    ..Widespread transcriptional dysfunction occurs in brains of Huntington's disease patients and in transgenic mouse and cell models of Huntington's disease...
  23. ncbi Homozygotes and heterozygotes for ciliary neurotrophic factor null alleles do not show earlier onset of Huntington's disease
    D C Rubinsztein
    Department of Medical Genetics, Addenbrooke s Hospital, Cambridge, UK
    Neurology 49:890-2. 1997
    ..We failed to detect an earlier onset of HD in nine homozygotes and 71 heterozygotes with this CNTF mutation compared with 203 homozygotes with wild-type alleles...
  24. pmc The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity
    M Lichtenberg
    Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 0XY, UK
    Cell Death Dis 2:e196. 2011
    ..Thus, we provide a molecular link between LRRK2, the most common known cause of PD, and its previously described phenotype of protein accumulation...
  25. ncbi Ascertainment bias cannot entirely account for human microsatellites being longer than their chimpanzee homologues
    G Cooper
    University of Cambridge, Department of Zoology, Downing Street, Cambridge CB2 3EJ, UK
    Hum Mol Genet 7:1425-9. 1998
    ..2 repeat units longer in humans than in chimpanzees, implying a mutational bias in favour of microsatellite expansions and a higher average genome-wide microsatellite mutation rate in the human lineage...
  26. ncbi The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer's disease
    T Murphy
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, UK
    Neuroreport 12:631-4. 2001
    ..Thus, we find no evidence that this locus influences risk for late-onset AD...
  27. pmc A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease
    C Tysoe
    Department of Medical Genetics, Addenbrooke s NHS Trust, Cambridge, CB2 2QQ, United Kingdom
    Am J Hum Genet 62:70-6. 1998
    ..Since no other mutations or polymorphisms were detected in our patients, mutations in the coding regions and splice consensus sequences of PS-1 are likely to be rare in EOAD cases unselected for family history...
  28. pmc A new locus for autosomal dominant "pure" hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity
    E Reid
    Department of Medical Genetics, University of Cambridge, Cambridge CB2 2XY, United Kingdom
    Am J Hum Genet 65:757-63. 1999
    ..2-cM region between markers D12S368 and D12S83. In addition, our data strongly suggest that there are at least six ADPHSP loci, since we describe a further family in which linkage to all five known ADPHSP loci has been excluded...
  29. ncbi A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases
    R A Furlong
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    Neurosci Lett 277:123-6. 1999
    ..The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder...
  30. ncbi Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence
    D C Rubinsztein
    East Anglian Regional Genetics Service Molecular Genetics Laboratory, Addenbrooke s NHS Trust, Cambridge, UK
    Nat Genet 7:525-30. 1994
    ..The key element is a simple length-dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever-increasing incidence of HD...
  31. ncbi Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans
    C S Hanlon
    East Anglian Regional Genetics Service, Addenbrooke s NHS Trust, Cambridge, UK
    Atherosclerosis 112:85-90. 1995
    ..All were similar to apo E4. This suggests that apo E4 is the ancestral allele and that apo E2 and apo E3 arose after the split of the human and chimpanzee lineages...
  32. ncbi Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity
    L Clark
    Department of Experimental Psychology, University of Cambridge, Downing Street, and Department of Medical Genetics, Addenbrooke s Hospital, Cambridge, UK
    Psychopharmacology (Berl) 182:570-8. 2005
    ..Reduced serotonin neurotransmission is implicated in disorders of impulse control, but the involvement of serotonin in inhibitory processes in healthy human subjects remains unclear...
  33. pmc Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL
    S Luo
    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    Cell Death Differ 17:268-77. 2010
    ..The cleavage of Beclin 1 is a critical event whereby caspases inhibit autophagy, as a non-cleavable Beclin 1 mutant restored autophagy in cells overexpressing Bax...
  34. 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
    ....
  35. 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...
  36. 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...
  37. 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
    ....
  38. 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...
  39. 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...
  40. 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...
  41. 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...
  42. 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...
  43. 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
    ....
  44. 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...
  45. 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...
  46. 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...
  47. 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...
  48. 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...
  49. 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...
  50. 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...
  51. 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...
  52. 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...
  53. 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)...
  54. 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...
  55. 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...
  56. 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...
  57. 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...
  58. 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...
  59. 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
    ....
  60. 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...
  61. 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
    ....
  62. 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...
  63. 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...
  64. 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...
  65. 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...
  66. 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...
  67. 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...
  68. 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...
  69. 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...
  70. 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
    ....
  71. 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...
  72. 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
    ....
  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 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...
  75. 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...
  76. 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...
  77. 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
    ....
  78. 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
  79. 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...
  80. 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
    ....
  81. 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...
  82. 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...
  83. 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...
  84. 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...
  85. 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...
  86. 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...
  87. 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
    ....
  88. 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...
  89. 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...