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  • Cohen, Samuel I A (author)

A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.

  • Article/chapterEnglish2015

Publisher, publication year, extent ...

  • 2015-02-16
  • Springer Science and Business Media LLC,2015

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:30a97378-e770-4e29-8a9d-847088245d1c
  • https://lup.lub.lu.se/record/5143557URI
  • https://doi.org/10.1038/nsmb.2971DOI
  • https://res.slu.se/id/publ/76073URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:130873608URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Arosio, Paolo (author)
  • Presto, JennyKarolinska Institutet (author)
  • Kurudenkandy, Firoz RoshanKarolinska Institutet (author)
  • Biverstål, HenrikKarolinska Institutet (author)
  • Dolfe, LisaKarolinska Institutet (author)
  • Dunning, ChristopherLund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups(Swepub:lu)med-cdn (author)
  • Yang, Xiaoting (author)
  • Frohm, Birgitta (author)
  • Vendruscolo, Michele (author)
  • Johansson, JanKarolinska Institutet,Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för anatomi, fysiologi och biokemi,Department of Anatomy, Physiology and Biochemistry (AFB),Tallinn University(Swepub:slu)47966 (author)
  • Dobson, Christopher M (author)
  • Fisahn, AndréKarolinska Institutet (author)
  • Knowles, Tuomas P J (author)
  • Linse, Sara (author)
  • Karolinska InstitutetKlinisk minnesforskning (creator_code:org_t)
  • Sveriges lantbruksuniversitet

Related titles

  • In:Nature Structural & Molecular Biology: Springer Science and Business Media LLC22:3, s. 207-2131545-99851545-9993

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