Human Molecular Genetics, Vol 7, 379-384, Copyright © 1998 by Oxford University Press
A Abdullah, MA Trifiro, V Panet-Raymond, C Alvarado, S de Tourreil, D Frankel, HM Schipper and L Pinsky
The neuronotoxicity of genes with expanded CAG repeats is most likely
mediated by their respective polyglutamine (Gln)-expanded gene products.
Gln- expanded portions of these products may be sufficient, or necessary,
for pathogenesis. We tested whether a Gln-expanded human androgen receptor
(AR) is structurally altered, so that it allows for the proteolytic
generation of a potentially pathogenic portion that may be resistant to
further degradation. We found, in vitro , that a Gln- expanded AR is more
proteolytically resistant than normal, and that it yields a distinct set of
Gln-expanded fragments even after extended proteolysis in the presence of 2
M urea. Furthermore, COS cells transfected with CAG-expanded AR cDNA
generate an aberrant, nuclear- associated 75 kDa derivative containing the
Gln-expanded tract. They are also twice as likely to die by 24 h
apoptotically than those transfected with normal AR cDNA. Our data support
the notion that an unconventional derivative of the Gln- expanded AR is a
component of the proximate motor neuronopathic agent in spinobulbar
muscular atrophy. They also focus attention on two ways in which
neuronotoxic derivatives may originate from various Gln-expanded proteins:
(i) generation of an unusual derivative that is pathogenic de novo ; and
(ii) the toxic accumulation of a normal derivative because of an inability
to dispose of it.
ARTICLES
Spinobulbar muscular atrophy: polyglutamine-expanded androgen receptor is proteolytically resistant in vitro and processed abnormally in transfected cells
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
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