Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Protein misfolding and aggregation are implicated in neurodegenerative diseases like Alzheimer's.
• Amyloid-β (Aβ) peptide misfolding leads to neurotoxic oligomers and amyloid fibrils.
• The Bri2 protein's BRICHOS domain modulates Aβ aggregation and neurotoxicity.

Purpose of the Study:

• To elucidate the mechanisms by which Bri2 BRICHOS domain mediates its diverse effects on protein aggregation and toxicity.
• To investigate the distinct roles of Bri2 BRICHOS monomers versus dimers in modulating Aβ pathology.

Main Methods:

• In vitro assays to assess Aβ neurotoxicity and fibril formation.
• Structural analysis of Bri2 BRICHOS dimers.
• In vivo Drosophila models for neurodegenerative disease.

Main Results:

• Bri2 BRICHOS monomers effectively prevent Aβ-induced neuronal network toxicity.
• Bri2 BRICHOS dimers strongly inhibit Aβ fibril formation.
• Dimers form symmetrical oligomers that inhibit non-fibrillar protein aggregation.

Conclusions:

• Bri2 BRICHOS protein utilizes distinct quaternary structures (monomers and dimers) to target different aspects of protein misfolding.
• This structural plasticity suggests a mechanism for generating diverse molecular chaperone activities.
• Findings offer insights into therapeutic strategies for protein misfolding diseases.