Protein aggregation in Huntington's disease.
The presence of an expanded polyglutamine produces a toxic gain of function in huntingtin. Protein aggregation resulting from this gain of function is likely to be the cause of neuronal death. Two main mechanisms of aggregation have been proposed: hydrogen bonding by polar-zipper formation and covalent bonding by transglutaminase-catalyzed cross-linking. In cell culture models of Huntington's disease, aggregates are mostly stabilized by hydrogen bonds, but covalent bonds are also likely to occur. Nothing is known about the nature of the bonds that stabilize the aggregates in the brain of patients with Huntington's disease. It seems that the nature of the bond stabilizing the aggregates is one of the most important questions, as the answer would condition the therapeutic approach to Huntington's disease.
Hoffner
Guylaine
G
UPR 2228-CNRS, Institut Interdisciplinaire des Sciences du Vivant des Saints-Pères, Université René-Descartes, 45, rue des Saints-Pères, 75270 cedex 6, Paris, France.
Djian
Philippe
P
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology / Q000378:metabolism*; D002479:Inclusion Bodies / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D011503:Transglutaminases / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine; D011503:Transglutaminases