Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease - Archive ouverte HAL Access content directly
Journal Articles Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences (1934–1990) Year : 1999

Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease

Abstract

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 to 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.

Dates and versions

hal-03503628 , version 1 (28-12-2021)

Identifiers

Cite

Astrid Lunkes, Yvon Trottier, Jerôme Fagart, Patrick Schultz, Gabrielle Zeder-Lutz, et al.. Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences (1934–1990), 1999, 354 (1386), pp.1013-1019. ⟨10.1098/rstb.1999.0453⟩. ⟨hal-03503628⟩
8 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More