Caspases in Huntington’s Disease

Huntington’s disease (HD) is an autosomal dominant condition, resulting from a mutation in huntingtin (htt). Htt is a novel protein, and its normal function is at present not well understood. Nuclear translocation of mutant htt in vitro up-regulates expression of the cell death gene caspase-1. We have demonstrated in a transgenic HD mouse model that caspase-1 and caspase-3 are transcriptionally up-regulated and activated. Underscoring the relevancy of these findings, recent results suggest that caspase-1 is activated in brains of humans with HD. Caspase activation results in the proteolytic cleavage of key cellular targets, including htt, leading to cell dysfunction. Caspase activation leading to cell dysfunction and death correlates with disease progression. In HD-transgenic mice, caspase inhibition resulted in a delayed onset of symptoms, a slowed progression, and prolonged survival. Caspase inhibition is a therapeutic strategy that merits evaluation in humans with HD.

[1]  S. Hersch,et al.  Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease , 2000, Nature Medicine.

[2]  D. Tagle,et al.  Mutant Huntingtin Expression in Clonal Striatal Cells: Dissociation of Inclusion Formation and Neuronal Survival by Caspase Inhibition , 1999, The Journal of Neuroscience.

[3]  Y. Kawaoka,et al.  Epidermal immunization by a needle-free powder delivery technology: Immunogenicity of influenza vaccine and protection in mice , 2000, Nature Medicine.

[4]  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.

[5]  M. Chesselet,et al.  Tissue-Specific Proteolysis of Huntingtin (htt) in Human Brain: Evidence of Enhanced Levels of N- and C-Terminal htt Fragments in Huntington's Disease Striatum , 2001, The Journal of Neuroscience.

[6]  Michael S. Levine,et al.  Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice , 2000, Nature Genetics.

[7]  J. B. Martin,et al.  Molecular basis of the neurodegenerative disorders. , 1999, The New England journal of medicine.

[8]  Shai Shaham,et al.  The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme , 1993, Cell.

[9]  S. Hersch,et al.  Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Christopher A Ross,et al.  Widespread expression of Huntington's disease gene (IT15) protein product , 1995, Neuron.

[11]  Ole A. Andreassen,et al.  Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease , 2000, The Journal of Neuroscience.

[12]  S. Tabrizi,et al.  Biochemical abnormalities and excitotoxicity in Huntington's disease brain , 1999, Annals of neurology.

[13]  P. Brundin,et al.  Recent Advances on the Pathogenesis of Huntington's Disease , 1999, Experimental Neurology.

[14]  J. D. den Dunnen,et al.  Subcellular localization of the Huntington's disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. , 1996, Human molecular genetics.

[15]  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.

[16]  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.

[17]  J. Hodgson,et al.  Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. , 2001, American journal of human genetics.

[18]  M. MacDonald,et al.  Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease , 1993, Nature Genetics.

[19]  R. Carraway,et al.  Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons , 1995, Neuron.

[20]  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.

[21]  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.

[22]  M. Kaul,et al.  Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury , 2000, Neuroscience.

[23]  X. Li,et al.  Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. , 2000, Human molecular genetics.

[24]  M. Moskowitz,et al.  Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury , 1997, The Journal of experimental medicine.

[25]  H. Lipkin.  Where is the ?c? , 1978 .

[26]  P. Stieg,et al.  Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. , 2000, Science.

[27]  C. Portera-Cailliau,et al.  Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  R. Albin,et al.  Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues , 1993, Nature Genetics.

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

[30]  E. Hirsch,et al.  Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form , 1995, Nature Genetics.

[31]  M. Hayden,et al.  The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease , 1993, Nature Genetics.

[32]  M. MacDonald,et al.  Heterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum , 1997, The Journal of Neuroscience.

[33]  M. Dubois‐Dauphin,et al.  Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis , 2000, The Journal of Neuroscience.

[34]  Junying Yuan,et al.  Apoptosis in the nervous system , 2000, Nature.

[35]  Dale E. Bredesen,et al.  Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract* , 1998, The Journal of Biological Chemistry.

[36]  R. Friedlander,et al.  Role of caspase 1 in neurologic disease. , 2000, Archives of neurology.

[37]  A. Hackam,et al.  Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3 , 2000, The Journal of Neuroscience.

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

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

[40]  J. Penney,et al.  Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease , 1999, Nature.

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

[42]  O. Andreassen,et al.  Malonate and 3‐Nitropropionic Acid Neurotoxicity Are Reduced in Transgenic Mice Expressing a Caspase‐1 Dominant‐Negative Mutant , 2000, Journal of neurochemistry.

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

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

[45]  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.

[46]  M. Moskowitz,et al.  Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Michael R. Hayden,et al.  The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity , 1998, The Journal of cell biology.

[48]  M. DiFiglia,et al.  Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy , 2000, The Journal of Neuroscience.

[49]  P. Chan,et al.  A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Young,et al.  A polymorphic DNA marker genetically linked to Huntington's disease , 1983, Nature.

[51]  V. Ona,et al.  Minocycline Reduces Traumatic Brain Injury-mediated Caspase-1 Activation, Tissue Damage, and Neurological Dysfunction , 2001, Neurosurgery.

[52]  Nahida Matta,et al.  CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain , 1995, Neuron.

[53]  M. Hayden,et al.  Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract , 1996, Nature Genetics.

[54]  D. Cleveland,et al.  Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.