A. Lunkes et al., Properties of polyglutamine expansion in vitro and in a cellular model forHuntington's disease, PHI T ROY B, 354(1386), 1999, pp. 1013-1019
Citations number
38
Categorie Soggetti
Multidisciplinary,"Experimental Biology
Journal title
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
Eight neurodegenerative diseases have been shown to be caused by the expans
ion of a polyglutamine stretch in specific target proteins that lead to a g
ain in toxic property. Most of these diseases have some features in common.
A pathological threshold of 35-40 glutamine residues is observed in five o
f the diseases. The mutated proteins (or a polyglutamine-containing subfrag
ment) form ubiquitinated aggregates in neurons of patients or mouse models,
in most cases within the nucleus. We summarize the properties of a monoclo
nal antibody that recognizes specifically, in a Western blot, polyglutamine
stretches longer than 35 glutamine residues with an affinity that increase
s 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 ca
rrying 38 glutamine residues is able to aggregate into regular fibrils in v
itro. Finally, we present a cellular model in which the induced expression
of a mutated full-length huntingtin protein leads to the formation of nucle
ar inclusions that share many characteristics with those observed in patien
ts: those inclusions are ubiquitinated and contain only an N-terminal fragm
ent of huntingtin. This model should thus be useful in studying a processin
g step that is likely to be important in the pathogenicity of mutated hunti
ngtin.