A molecular chaperone breaks the catalytic cycle that generates toxic A beta oligomers

Sammanfattning

Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-beta peptide (A beta 42). Recent studies have revealed that once A beta 42 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 A beta 42 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.

Publicerad i

Nature Structural and Molecular Biology
2015, volym: 22, nummer: 3, sidor: 207-213
Utgivare: NATURE PUBLISHING GROUP

SLU författare

• Johansson, Jan

  • Institutionen för husdjurens biovetenskaper, Sveriges lantbruksuniversitet
    
  • Tallinna Ülikool

UKÄ forskningsämne

Biokemi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Molekylärbiologi

Publikationens identifierare

• DOI: https://doi.org/10.1038/nsmb.2971

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/76073