Biochemistry
Biochemistry
5 years ago

Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils

Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils
Myles C. Isas, J. Mario Isas, Nitin K. Pandey, Andreas Langen, Ansgar B. Siemer
The fact that the heritable neurodegenerative disorder Huntington’s disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTTex1) that causes the disease leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1 into amyloid fibrils, which in turn can seed the fibril formation of mutant HTTex1. Solid-state NMR and electron paramagnetic resonance data showed that wild type HTTex1 fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTTex1 monomers have a much higher equilibrium solubility compared to mutant HTTex1, and only a small fraction incorporates into fibrils.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00138

DOI: 10.1021/acs.biochem.7b00138

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.