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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 8 ·1999-04-13 ·Pages 4604-9

Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE

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.

MeSH Terms

Amino Acid Sequence Amyloid/metabolism,ultrastructure Animals COS Cells Cloning, Molecular Escherichia coli Humans Huntingtin Protein Huntington Disease/metabolism,pathology Molecular Sequence Data Nerve Tissue Proteins/biosynthesis,chemistry Nuclear Proteins/biosynthesis,chemistry Peptide Fragments/metabolism Peptides/metabolism Recombinant Proteins/chemistry,metabolism Transfection

Chemicals

Amyloid HTT protein, human Huntingtin Protein Nerve Tissue Proteins Nuclear Proteins Peptide Fragments Peptides Recombinant Proteins polyglutamine

Authors & Affiliations

9 authors, click to expand affiliations / ORCID

Scherzinger E

Max-Planck-Institut für Molekulare Genetik, D-14195 Berlin (Dahlem), Germany.

Sittler A

Schweiger K

Heiser V

Lurz R

Hasenbank R

Bates G P

Lehrach H

Wanker E E

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.96.8.4604

Published

1999-04-13

Pages

4604-9

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC16379

Subset

External Links

PubMed source DOI: 10.1073/pnas.96.8.4604 PMC Full Text View journal details

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

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