A molecular perspective of gelsolin amyloidosis: An old foe with new faces

Hereditary gelsolin amyloidosis (AGel) is a rare and often underrecognized protein misfolding disorder caused by mutations in the gelsolin (GSN) protein, leading to its aggregation in various tissues. Its rarity, combined with a heterogeneous and complex clinical presentation and the multidomain, flexible nature of GSN, has impeded research into its pathogenic mechanisms and therapeutic options. GSN comprises six homologous domains, labeled sequentially from G1 to G6. For over 40 years, AGel amyloidosis was exclusively linked to a systemic form, caused by D187N and D187Y mutations in the second domain, referred to as the Finnish and Danish variants. However, since 2013, numerous novel amyloidogenic variants have been identified in different protein regions, leading to various clinical phenotypes, characterized by distinct molecular mechanisms. This review examines these mutations and proposes a classification based on molecular and clinical features to enhance research and diagnosis. Additionally, we summarize whether elucidating the different pathogenic mechanisms aids in identifying potential druggable targets. The lack of information and biological models and limited efforts to develop pharmacological treatments highlight the need for further therapeutic exploration.