Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease.
Eight neurodegenerative diseases have been shown to be caused by the expansion of a polyglutamine stretch in specific target proteins that lead to a gain in toxic property. Most of these diseases have some features in common. A pathological threshold of 35-40 glutamine residues is observed in five of the diseases. The mutated proteins (or a polyglutamine-containing subfragment) form ubiquitinated aggregates in neurons of patients or mouse models, in most cases within the nucleus. We summarize the properties of a monoclonal antibody that recognizes specifically, in a Western blot, polyglutamine stretches longer than 35 glutamine residues with an affinity that increases with polyglutamine length. This indicates that the pathological threshold observed in five diseases corresponds to a conformational change creating a pathological epitope, most probably involved in the aggregation property of the carrier protein. We also show that a fragment of a normal protein carrying 38 glutamine residues is able to aggregate into regular fibrils in vitro. Finally, we present a cellular model in which the induced expression of a mutated full-length huntingtin protein leads to the formation of nuclear inclusions that share many characteristics with those observed in patients: those inclusions are ubiquitinated and contain only an N-terminal fragment of huntingtin. This model should thus be useful in studying a processing step that is likely to be important in the pathogenicity of mutated huntingtin.
Lunkes
A
A
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, Illkirch, CU de Strasbourg, France.
Trottier
Y
Y
Fagart
J
J
Schultz
P
P
Zeder-Lutz
G
G
Moras
D
D
Mandel
J L
JL
D000818:Animals; D002467:Cell Nucleus / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D002479:Inclusion Bodies / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D011487:Protein Conformation; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine