Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington's Disease

Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible.

[1]  S. W. Davies,et al.  From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[2]  C A Ross,et al.  Intranuclear Neuronal Inclusions: A Common Pathogenic Mechanism for Glutamine-Repeat Neurodegenerative Diseases? , 1997, Neuron.

[3]  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.

[4]  H. Zoghbi,et al.  The CAG/Polyglutamine Tract Diseases: Gene Products and Molecular Pathogenesis , 1997, Brain pathology.

[5]  R. Ferrante,et al.  Neuropathological Classification of Huntington's Disease , 1985, Journal of neuropathology and experimental neurology.

[6]  L. Bäckman,et al.  Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. , 1997, Brain : a journal of neurology.

[7]  J. Penney,et al.  Homozygotes for Huntington's disease , 1987, Nature.

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

[9]  O. Hansson,et al.  Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Augood,et al.  Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease , 1997, Annals of neurology.

[11]  R. Hen,et al.  Absence of Fenfluramine-Induced Anorexia and Reduced c-fos Induction in the Hypothalamus and Central Amygdaloid Complex of Serotonin 1B Receptor Knock-Out Mice , 1998, The Journal of Neuroscience.

[12]  R Hen,et al.  Differential addressing of 5-HT1A and 5-HT1B receptors in epithelial cells and neurons. , 1999, Journal of cell science.

[13]  G P Bates,et al.  Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. , 1999, Human molecular genetics.

[14]  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.

[15]  Jacqueline K. White,et al.  Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion , 1997, Nature Genetics.

[16]  P. Demoly,et al.  [Transgenic mice]. , 1992, Annales de dermatologie et de venereologie.

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

[18]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[19]  Jacqueline K. White,et al.  Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. , 1999, Human molecular genetics.

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

[21]  S. K. Malhotra,et al.  Reactive astrocytes: cellular and molecular cues to biological function , 1997, Trends in Neurosciences.

[22]  M. Gossen,et al.  Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Durbin,et al.  Structure and expression of the Huntington's disease gene: Evidence against simple inactivation due to an expanded CAG repeat , 1994, Somatic cell and molecular genetics.

[24]  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.

[25]  L. Blackmore.  Cognitive deficits in Huntington's disease , 1993 .

[26]  M. Gossen,et al.  Use of tetracycline-controlled gene expression systems to study mammalian cell cycle. , 1997, Methods in enzymology.

[27]  J. Cummings,et al.  Huntington's disease. , 1997, The Psychiatric clinics of North America.

[28]  R H Myers,et al.  Decreased Neuronal and Increased Oligodendroglial Densities in Huntington's Disease Caudate Nucleus , 1991, Journal of neuropathology and experimental neurology.

[29]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[30]  Steven Finkbeiner,et al.  Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions , 1998, Cell.

[31]  P. Lansbury.  Structural Neurology: Are Seeds at the Root of Neuronal Degeneration? , 1997, Neuron.

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

[33]  Virginia E. Papaioannou,et al.  Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue , 1995, Nature Genetics.

[34]  S. Folstein,et al.  Early Loss of Neostriatal Striosome Neurons in Huntington's Disease , 1995, Journal of neuropathology and experimental neurology.

[35]  Lisa Garrett,et al.  Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA , 1998, Nature Genetics.

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

[37]  M. MacDonald,et al.  Normal and Expanded Huntington’s Disease Gene Alleles Produce Distinguishable Proteins Due to Translation Across the CAG Repeat , 1995, Molecular medicine.

[38]  A. Joyner,et al.  Inactivation of the mouse Huntington's disease gene homolog Hdh. , 1995, Science.

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

[40]  Carlos Cepeda,et al.  Enhanced sensitivity to N‐methyl‐D‐aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease , 1999, Journal of neuroscience research.

[41]  S. Floresco,et al.  Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes , 1995, Cell.

[42]  S. W. Davies,et al.  Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[43]  J. Brandt,et al.  Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at‐risk persons , 1994, Neurology.

[44]  R. Myers,et al.  Impaired synaptic plasticity in mice carrying the Huntington's disease mutation. , 1999, Human molecular genetics.

[45]  Ronald Bontrop,et al.  Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence , 1994, Nature Genetics.

[46]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[47]  D. Brooks,et al.  Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study. , 1995, Brain : a journal of neurology.

[48]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Claire-Anne Gutekunst,et al.  A YAC Mouse Model for Huntington’s Disease with Full-Length Mutant Huntingtin, Cytoplasmic Toxicity, and Selective Striatal Neurodegeneration , 1999, Neuron.

[50]  M. Gossen,et al.  Co-regulation of two gene activities by tetracycline via a bidirectional promoter. , 1995, Nucleic acids research.

[51]  M. Figueiredo-Pereira,et al.  Ubiquitin, cellular inclusions and their role in neurodegeneration , 1998, Trends in Neurosciences.

[52]  G. M. Halliday,et al.  Regional Specificity of Brain Atrophy in Huntington's Disease , 1998, Experimental Neurology.

[53]  J. Gusella,et al.  Huntington's disease. Pathogenesis and management. , 1986, The New England journal of medicine.

[54]  M. Gossen,et al.  Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. W. Davies,et al.  Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.