BMI SEMINAR // Magdalini Polymenidou - Untangling ALS and FTLD pathogenesis: from molecular structures to ageing neural systems

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia FTD are fatal and incurable neurodegenerative diseases, characterized by accumulation of pathologic forms of RNA-binding proteins, most frequently TDP-43 and FUS. The molecular triggers of TDP-43 and aggregation, the basis of disease heterogeneity and the mechanisms of neurotoxicity remain elusive. To address these important questions, we study the formation and properties of the physiological and pathological states of these proteins in patient samples and disease cellular and animal models. Combining structural protein analysis with cellular systems we uncovered a novel and unexpected mechanism that counteracts pathologic aggregation of TDP-43 (1). We recently discovered that ALS and FTD heterogeneity is associated with alternate pathological TDP-43 conformations, reminiscent of prion strains (2). Moreover, we have described a trigger for the initial cytoplasmic mislocalization of FUS, likely occurring in sporadic FTD-FUS patients (3). The implications of all this work and its potential for gaining mechanistic insights on disease will be discussed.