Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology

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Item Type:	Article
Title:	Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology
Creators Name:	Scherzinger, E., Sittler, A., Schweiger, K., Heiser, V., Lurz, R., Hasenbank, R., Bates, G.P., Lehrach, H. and Wanker, E.E.
Abstract:	Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine [poly(Q)] repeat expansion in the first exon of the huntingtin protein. Previously, we showed that N-terminal huntingtin peptides with poly(Q) tracts in the pathological range (51-122 glutamines), but not with poly(Q) tracts in the normal range (20 and 30 glutamines), form high molecular weight protein aggregates with a fibrillar or ribbon-like morphology, reminiscent of scrapie prion rods and beta-amyloid fibrils in Alzheimer's disease. Here we report that the formation of amyloid-like huntingtin aggregates in vitro not only depends on poly(Q) repeat length but also critically depends on protein concentration and time. Furthermore, the in vitro aggregation of huntingtin can be seeded by preformed fibrils. Together, these results suggest that amyloid fibrillogenesis in Huntington's disease, like in Alzheimer's disease, is a nucleation-dependent polymerization.
Keywords:	Amino Acid Sequence, Amyloid, COS Cells, Molecular Cloning, Escherichia coli, Huntington Disease, Molecular Sequence Data, Nerve Tissue Proteins, Nuclear Proteins, Peptide Fragments, Peptides, Recombinant Proteins, Transfection, Animals
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	96
Number:	8
Page Range:	4604-4609
Date:	13 April 1999
Official Publication:	https://doi.org/10.1073/pnas.96.8.4604
PubMed:	View item in PubMed

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