AbstractsBiology & Animal Science

Amyloid diseases involve specific protein misfolding events and formation of fibrillar deposits. The symptoms of these diseases are broad and dependent on site of accumulation, with different amyloid proteins depositing in specific tissues or systematically. One such protein is transthyretin (TTR) associated with senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. We show that the glycosaminoglycan heparan sulfate (HS) can be co-localized with TTR in elder myopathic heart tissue and identify residue 24-35 of TTR as the binding site of HS. Moreover, we show that heparin, a HS homolog, can promote fibril formation and accumulation of TTR using cell cultures and a Drosophila in vivo model. It has been shown that certain chaperones are associated with amyloid disease and can promote or inhibit the aggregation into amyloid. BRICHOS is an approximately 100 residue protein domain present in over a 1000 proteins divided into 10 families. BRICHOS containing proteins have been ascribed a wide variety of functions and some are associated with diseases such as respiratory distress syndrome, dementia and cancer. The BRICHOS domains of proSP-C, a precursor protein to lung surfactant protein C, and Bri2, a protein associated with familial British and Danish dementia, can act as chaperones and inhibit amyloid fibril formation of the amyloid-β peptide (Aβ) of Alzheimer’s disease (AD). We show that both proSP-C and Bri2 BRICHOS can prevent aggregation of Aβ in vivo using Drosophila melanogaster as a model organism. Moreover, BRICHOS can inhibit the toxicity of Aβ, increasing the life span and locomotor activity of the flies. We also identify expression of Bri2 in human pancreas and show that Bri2 co-localizes with the islet amyloid polypeptide (IAPP) linked to type 2 diabetes (T2D). Furthermore, Bri2 BRICHOS can inhibit the aggregation of IAPP in vitro and reduce the toxic effects of IAPP in cell cultures and in vivo in a Drosophila model. These results show that the BRICHOS domain inhibits the aggregation and toxicity of both Aβ and IAPP. The BRICHOS domain, in particular the Bri2 BRICHOS domain, could be used as a potential pharmaceutical agent in treatment of amyloid diseases. Similar effects on both Aβ and IAPP suggest that the BRICHOS domain also could effect the amyloid formation and toxicity of other amyloid proteins, which would be an interesting area to further investigate.