title: Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases.
abstract: Huntington's disease (HD) is one of a number of familial polyglutamine (polyQ) repeat diseases. These neurodegenerative disorders are caused by expression of otherwise unrelated proteins that contain an expansion of a polyQ tract, rendering them toxic to specific subsets of vulnerable neurons. These expanded repeats have an inherent propensity to aggregate; insoluble neuronal nuclear and cytoplasmic polyQ aggregates or inclusions are hallmarks of the disorders [1,2]. In HD, inclusions in diseased brains often precede onset of symptoms, and have been proposed to be involved in pathogenicity [3-5]. Various strategies to block the process of aggregation have been developed in an effort to create drugs that decrease neurotoxicity. A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-4260, USA. jssteffa@uci.edu
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D042622:DNA Repeat Expansion; D029721:Drosophila Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics; D045586:Intranuclear Inclusion Bodies / Q000737:chemistry / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018832:Molecular Chaperones / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D020449:Repetitive Sequences, Amino Acid; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D029742:Caenorhabditis elegans Proteins; D015853:Cysteine Proteinase Inhibitors; D029721:Drosophila Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine