Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS

TY - JOUR

T1 - Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS

AU - Adam, Laurène

AU - Kumar, Rakesh

AU - Arroyo-Garcia, Luis Enrique

AU - Molenkamp, Willem Hendrik

AU - Nowak, Jan Stanislaw

AU - Klute, Hannah

AU - Farzadfard, Azad

AU - Alkenayeh, Rami

AU - Nielsen, Janni

AU - Biverstål, Henrik

AU - Otzen, Daniel E

AU - Johansson, Jan

AU - Abelein, Axel

N1 - © 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.

PY - 2024/8

Y1 - 2024/8

N2 - Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson's disease, where new therapeutic approaches remain essential to combat these devastating diseases. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominantly suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), decreasing the oligomer generation rate. Further, BRICHOS directly binds to oligomeric αSyn species and effectively diminishes αSyn fibril-related toxicity. Hence, our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.

AB - Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson's disease, where new therapeutic approaches remain essential to combat these devastating diseases. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominantly suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), decreasing the oligomer generation rate. Further, BRICHOS directly binds to oligomeric αSyn species and effectively diminishes αSyn fibril-related toxicity. Hence, our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.

KW - Adaptor Proteins, Signal Transducing/chemistry

KW - Humans

KW - Molecular Chaperones/chemistry

KW - Protein Domains

KW - alpha-Synuclein/chemistry

UR - http://www.scopus.com/inward/record.url?scp=85197813733&partnerID=8YFLogxK

U2 - 10.1002/pro.5091

DO - 10.1002/pro.5091

M3 - Journal article

C2 - 38980078

SN - 0961-8368

VL - 33

JO - Protein Science

JF - Protein Science

IS - 8

M1 - e5091

ER -