Identification of structural determinants of light chain amyloidosis

Immunoglobulin light chain amyloidosis (AL) is a systemic and progressive disease associated with the aggregation of light chains(LC) in form of amyloid fibrils. AL can affect virtually any organ, although kidney and heart involvement are the most common accounting for 46% and 30% of the cases, respectively. Cardiac involvement is particularly threatening due to its rapid progression and the bad prognosis. The exceptional diversification of tissues affected by amyloidosis and the molecular basis of LC toxicity are the subject of active research since decades, but, unfortunately, a comprehensive picture of the causes of this disease is still missing. Several clinical studies suggest that not the deposition of finalfibril, but the presence of transient oligomeric species during amyloid fibril formation is responsible for the development of organ dysfunction. In fact, it has been recognized that after LCs production interruption by chemotherapy, albeit before amyloid deposit clearance, there is a significant improvement in conditions involving renal and cardiac amyloidosis. During antibody production light chains are usually over-expressed, in comparison to heavy chains, and secreted as free chains. Under physiological conditions, LCs can be present as monomers and/or dimers, called Bence Jones (BJ) proteins, even in healthy subjects. In recent studies, it has been pointed out that BJ proteins are protective against aggregation. The LC toxicity might, therefore, be the consequence of the destabilization of BJ proteins and the cleavage of the variable domain of LC by proteases, together with different internalization propensities associated to various oligomeric states. The broad aim of this research project is, therefore, to study the correlation between cellular toxicity and structural features of immunoglobulin light chains such as (1) BJ and $V_L$ dimerstability, (2) flexibility of LC monomers, (3) accessibility to proteases and (4) amyloid propensity. In order to achieve this goal, we will develop methods for the rapid and accurate modeling of LC and BJ proteins and perform extensive molecular dynamics simulations to compute this quantities on a large database of toxic and non-toxic sequences. In addition to that, we will search for small-molecules that could stabilize the interaction between the light chains in BJ proteins and, thus, act as potential therapeutics. We envisage that the research project proposed here could have an impact on the development of novel, safer therapeutics for the treatment of light chain amyloidosis and deepen our understanding of the molecular basis of this severe disease.