Potential mechanism of xenobiotic seeding of TGFBIp fibrils and modified brain chaperones as therapy for TGFBI-associated corneal dystrophies

Abstract

Transforming growth factor beta induced protein (TGFBIp) in the cornea undergoes proteolytic processing to produce peptides of uncertain physiological function with hereditary isoforms of the peptides giving rise to amyloidogenic corneal dystrophies (CD). This study explored the coacervation propensity of wildtype TGFBIp peptides to inform on physiological function and ventured to optimize brain chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) for non-invasive TGFBIp- associated CD treatments. Coacervation of TGFBIp peptides were accessed through turbidites and bright-field imaging across pH, salt, molecular crowding and in the presence of pollutant 9,10- Phenanthrenequinone (9,10-PQ). TGFBIp peptide E611PVAEPDIMATNGVVHVITNVLQ633 was observed to form droplets in the presence of 9,10-PQ with prolonged exposure enhancing pathogenic fibrillation of the peptide. L-PGDS was mutated at C65 and K58 to supress off-target functions and improve disaggregation efficiency respectively. The novel RA-L-PGDS, harbouring both mutations, demonstrated improved function with predicted removal of prostaglandin D2 (PGD) synthase function and minimised membrane interactions. 9,10-PQ induced peptide coacervation is proposed to seed pathogenic fibrillation of wildtype TGFBIp peptides, indicating the capability of sporadic disease, potentially widening the prevalence of TGFBIp-associated CD. RA-L-PGDS with increased potency and potential safety can serve as an ideal candidate for non-surgical treatments for hereditary and likely environmentally induced TGFBIp-associated CD.