Janne Johansson

Institute:Department of Neurobiology, Care Sciences and Society; Karolinska Institute, Huddinge, Sweden
Title:Bri2 BRICHOS – a multitalented molecular chaperone with activity against amyloid-β toxicity in the central nervous system
Abstract:["The BRICHOS domain is found in human proproteins, including Bri2 and prosurfactant protein C (proSP-C). All BRICHOS containing proproteins share a common architecture. The BRICHOS domain is located in the ER lumen, and the proproteins contain specific regions with high beta-sheet propensity, which BRICHOS is believed to chaperone during biosynthesis. The finding that mutations in the BRICHOS domain of proSP-C result in lung amyloid composed of the beta-prone region supports this hypothesis. Bri2 is expressed in the CNS but also in peripheral tissues and mutations that extend its beta-prone region result in amyloid deposits and familial British and Danish dementia. Recombinant human (rh) BRICHOS domains from Bri2 or proSP-C reduce amyloid fibril formation and neurotoxicity of the amyloid beta-peptide associated with Alzheimer disease, and transgenic overexpression of BRICHOS reduces Abeta42 related pathology in fruit flies and mice. These findings suggest that BRICHOS domains are able to prevent fibril formation and toxicity of other clients than the beta-prone regions of their respective proprotein. Amyloid formation of islet amyloid polypeptide (IAPP) in islets of Langerhans is associated with type 2 diabetes and formation of toxic IAPP species is believed to contribute to the loss of insulin producing beta cells. Bri2 is expressed in human islets, colocalizes with IAPP and it is present in amyloid deposits in patients with type 2 diabetes. Rh Bri2 BRICHOS inhibits IAPP fibril formation in vitro and siRNA mediated reduction of endogenous Bri2 increases sensitivity to metabolic stress, while a concomitant over-expression of Bri2 BRICHOS is protective. These findings identify Bri2 BRICHOS as an important potential endogenous inhibitor of IAPP aggregation and toxicity. Bri2, but not proSP-C, BRICHOS domain prevents non-fibrillar aggregation of partly denatured proteins, raising the question how different activities of Bri2 BRICHOS are mediated. Isolated rh Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Abeta42, while dimers strongly suppress Abeta42 fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. Thus Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity."]
Host:Margreet Koopman (Cellular Protein Chemistry)