Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity

Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders.

[1]  D. Borchelt,et al.  Nuclear Accumulation of Truncated Atrophin-1 Fragments in a Transgenic Mouse Model of DRPLA , 1999, Neuron.

[2]  J T Finch,et al.  Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. MacDonald,et al.  Trinucleotide instability: a repeating theme in human inherited disorders. , 1996, Annual review of medicine.

[4]  M. Dragunow,et al.  Is CREB a key to neuronal survival? , 2000, Trends in Neurosciences.

[5]  D. Housman,et al.  The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  AC Tose Cell , 1993, Cell.

[7]  H. Bading,et al.  CBP: a signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV. , 1998, Science.

[8]  Harry T Orr,et al.  Ataxin-1 Nuclear Localization and Aggregation Role in Polyglutamine-Induced Disease in SCA1 Transgenic Mice , 1998, Cell.

[9]  A. Hackam,et al.  Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates , 1998, Nature Genetics.

[10]  Anirvan Ghosh,et al.  Regulation of CBP-Mediated Transcription by Neuronal Calcium Signaling , 1999, Neuron.

[11]  C A Ross,et al.  Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. , 2000, Human molecular genetics.

[12]  T. Dawson,et al.  Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity , 1998, The Journal of Neuroscience.

[13]  S. Ho,et al.  Site-directed mutagenesis by overlap extension using the polymerase chain reaction. , 1989, Gene.

[14]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[15]  D. Borchelt,et al.  Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. , 1999, Human molecular genetics.

[16]  Richard Threadgill,et al.  Regulation of Dendritic Growth and Remodeling by Rho, Rac, and Cdc42 , 1997, Neuron.

[17]  C. M. Davenport,et al.  Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. , 1999, Science.

[18]  John G. Gray,et al.  Medicine , 1902, Glasgow Medical Journal.

[19]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[20]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[21]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[22]  D. Storm,et al.  Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning , 1998, Nature Neuroscience.

[23]  H. Bading,et al.  Control of Recruitment and Transcription-Activating Function of CBP Determines Gene Regulation by NMDA Receptors and L-Type Calcium Channels , 1999, Neuron.

[24]  D. Housman,et al.  Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Housman Gain of glutamines, gain of function? , 1995, Nature Genetics.

[26]  E. Aylward,et al.  Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). , 1997, Medicine.

[27]  M. MacDonald,et al.  Mutant Huntingtin Forms in Vivo Complexes with Distinct Context-Dependent Conformations of the Polyglutamine Segment , 1999, Neurobiology of Disease.

[28]  I. Ferrer,et al.  Brain-derived neurotrophic factor in Huntington disease , 2000, Brain Research.

[29]  C. Ross,et al.  Nuclear Targeting of Mutant Huntingtin Increases Toxicity , 1999, Molecular and Cellular Neuroscience.

[30]  E. Richfield,et al.  Reduced expression of preproenkephalin in striatal neurons from huntington's disease patients , 1995, Annals of neurology.

[31]  K. Fischbeck,et al.  Intranuclear Inclusions of Expanded Polyglutamine Protein in Spinocerebellar Ataxia Type 3 , 1997, Neuron.

[32]  K. Fischbeck,et al.  Trinucleotide repeats in neurogenetic disorders. , 1996, Annual review of neuroscience.

[33]  D. Housman,et al.  Evidence for a recruitment and sequestration mechanism in Huntington's disease. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[34]  S. W. Davies,et al.  Intranuclear Neuronal Inclusions in Huntington's Disease and Dentatorubral and Pallidoluysian Atrophy: Correlation between the Density of Inclusions andIT15CAG Triplet Repeat Length , 1998, Neurobiology of Disease.

[35]  C A Ross,et al.  When more is less: Pathogenesis of glutamine repeat neurodegenerative diseases , 1995, Neuron.

[36]  M. MacDonald,et al.  Amyloid Formation by Mutant Huntingtin: Threshold, Progressivity and Recruitment of Normal Polyglutamine Proteins , 1998, Somatic cell and molecular genetics.

[37]  Masatoshi Hagiwara,et al.  Phosphorylated CREB binds specifically to the nuclear protein CBP , 1993, Nature.

[38]  C. Ross,et al.  Preparation of human cDNAs encoding expanded polyglutamine repeats , 1999, Neuroscience Letters.

[39]  S. W. Davies,et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. , 1997, Science.

[40]  I. Kanazawa,et al.  Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription , 2000, Nature Genetics.

[41]  C A Ross,et al.  Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. , 1998, Human molecular genetics.

[42]  Steven Finkbeiner,et al.  Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism , 1998, Neuron.

[43]  Max F. Perutz,et al.  Glutamine repeats and neurodegenerative diseases: molecular aspects. , 1999, Trends in biochemical sciences.

[44]  K. Fischbeck,et al.  CREB-binding protein sequestration by expanded polyglutamine. , 2000, Human molecular genetics.

[45]  Hans Lehrach,et al.  Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo , 1997, Cell.