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Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin - A potential mechanism for loss of huntingtin function in Huntington's disease

Item Type:Article
Title:Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin - A potential mechanism for loss of huntingtin function in Huntington's disease
Creators Name:Busch, A. and Engemann, S. and Lurz, R. and Okazawa, H. and Lehrach, H. and Wanker, E.E.
Abstract:Aggregation of huntingtin (htt) in neuronal inclusions is associated with the development of Huntington's disease (HD). Previously, we have shown that mutant htt fragments with polyglutamine (polyQ) tracts in the pathological range (>37 glutamines) form SDS-resistant aggregates with a fibrillar morphology, whereas wild-type htt fragments with normal polyQ domains do not aggregate. In this study we have investigated the coaggregation of mutant and wild-type htt fragments. We found that mutant htt promotes the aggregation of wild-type htt, causing the formation of SDS-resistant co-aggregates with a fibrillar morphology. Conversely, mutant htt does not promote the fibrillogenesis of the polyQ-containing protein NOCT3 or the polyQ-binding protein PQBP1, although these proteins are recruited into inclusions containing mutant htt aggregates in mammalian cells. The formation of mixed htt fibrils is a highly selective process that not only depends on polyQ tract length but also on the surrounding amino acid sequence. Our data suggest that mutant and wild-type htt fragments may also co-aggregate in neurons of HD patients and that a loss of wild-type htt function may contribute to HD pathogenesis.
Keywords:Carrier Proteins, Cell Line, COS Cells, Exons, Electron Microscopy, Fluorescence Microscopy, Glutathione Transferase, Green Fluorescent Proteins, Huntington Disease, Luminescent Proteins, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Peptides, Plasmids, Protein Binding, Recombinant Fusion Proteins, Time Factors, Transfection, Western Blotting, Animals
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:278
Number:42
Page Range:41452-41461
Date:17 October 2003
Official Publication:https://doi.org/10.1074/jbc.M303354200
PubMed:View item in PubMed

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