Gelsolin physiopathology

Gelsolin is the prototype of a superfamily of Ca2+-dependent proteins and it is responsible for the assembly, disassembly and scavenging of actin by means of its severing and capping activities. Due to its pivotal physiological activities and the ubiquity nature, gelsolin plays a main role in a plethora of physiological processes, such as cell motility and division, organelle trafficking and muscle contraction. Moreover, increasing evidence suggests a central role in cell metabolism and signaling, in an actin-independent fashion. As a consequence, alteration in gelsolin expression levels or deregulation of its activities have been observed in several diseases, cancers in particular. While the role of gelsolin in these pathological states is still to be elucidated, the protein is directly responsible for a rare disease, named gelsolin amyloidosis (AGel), caused by gain-of-toxic-function mutations. In AGel, misfolded protein aggregates and forms insoluble deposits, similarly to diseases such as ALS and Alzheimer’s. AGel has been for long considered an extremely rare disease, endemic only in few countries. In the last five years, AGel cases have been reported from all over the world, four new pathogenic mutations have been identified and a novel sporadic form of the disease described.
Integrating structural biology, biochemistry and biophysics techniques, this activity aims at elucidating the molecular bases of gelsolin-related diseases, with particular emphasis on AGel, and at providing a structural description of gelsolin physiological activities. In parallel, exploiting the same aforementioned methodologies we recently started a drug discovery project for the screening, optimization and validation of novel drugs against gelsolin-related diseases.



Fund(s): Telethon; Amyloidosis Foundation

Members:
Daniele Arosio
Michela Bollati
Patrizia Cioni
Matteo De Rosa (Principal investigator)
Toni Giorgino
Eloise Mastrangelo
Mario Milani