AL amyloidosis: gene restriction reveals the hidden molecular basis of amyloid transformation of immunoglobulin light chains

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Amyloidoses are diseases caused by the progressive deposition in target organs (heart, kidney, liver, soft tissues, peripheral and autonomic nervous system) of insoluble material consisting in proteins with an altered conformation. Light chain (AL) amyloidosis, in particular, is a rare and life-threatening form in which the aggregates derive from immunoglobulin light chains (LCs) (a portion of antibodies). Only LCs with specific sequences and encoded by particular genes (Such as TDark genes IGLV1-51 and IGLV6-57) cause amyloidosis, but the causal factors remain unknown. Current treatment (chemo and immunotherapies) target the LCs producing plasmacells; the scarce knowledge on the physiopathology of aggregation weakens the possibility to downstream strategies against aggregation. Starting from these considerations, and from the observation the the current experimental models do not adequately reproduce the features of natural amyloid deposits, this project aims at characterizing the mechanisms of aggregate formation in tissues, from IGLV1-51 and IGLV6-57 LCs, and to develop a compatible experimental model. The project will last 24 months and will be performed by 2 units with extensive experience in the molecular study of systemic amyloidoses, with numerous publications on high impact journals. Through a combination of biochemical and biophysical assays, structural proteomics, high resolution imaging and bioinformatics, we will test in particular the hypothesis that partial LCs degradation generates fragments more prone to aggregation, and that the interaction of LCs with other proteins may have a role in modulating this process. The results will cast light on the causal events in the formation of aggregates from LCs with a predisposing sequence, and will be crucial for creating a model that allows a reliable preclinical characterization of drugs, and for exploring novel targeted therapeutic strategies.