Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine

An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the...

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Vydáno v:	Nature medicine Ročník 8; číslo 2; s. 143 - 149
Hlavní autoři:	Karpuj, Marcela V., Becher, Mark W., Springer, Joe E., Chabas, Dorothee, Youssef, Sawsan, Pedotti, Rosetta, Mitchell, Dennis, Steinman, Lawrence
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.02.2002 Nature Publishing Group
Témata:	Animals Biomedical and Life Sciences Biomedicine Brain Brain - enzymology Cancer Research cystamine Cystamine - therapeutic use Dementia Dementia disorders Disease Enzyme Inhibitors - therapeutic use Enzymes Experiments Humans Huntington Disease - drug therapy Infectious Diseases Metabolic Diseases Mice Mice, Transgenic Molecular Medicine Movement Disorders - prevention & control Neurosciences Pathogenesis Survival Transgenic animals Transglutaminases - antagonists & inhibitors Transglutaminases - genetics Weight Loss - drug effects New Mexico United States > US
ISSN:	1078-8956, 1546-170X
On-line přístup:	Získat plný text
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Popis
Shrnutí:	An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the TGase competitive inhibitor, cystamine, to transgenic mice expressing exon 1 of huntingtin containing an expanded polyglutamine repeat, altered the course of their HD-like disease. Cystamine given intraperitoneally entered brain where it inhibited TGase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of one of the two genes shown to be neuroprotective for polyglutamine toxicity in Drosophila , dnaj (also known as HDJ1 and Hsp40 in humans and mice, respectively). Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	1078-8956 1546-170X
DOI:	10.1038/nm0202-143