Intracellular dynamics of disease-associated proteins in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is characterized by mislocalisation and aggregation of different disease-related proteins. In most ALS cases, the predominant pathological species are RNA-binding proteins (e.g. TDP-43 and FUS). Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. Our aim is to investigate how this pathological cascade is initiated. Recent breakthroughs point at a crucial role for the nucleocytoplasmic transport system. In addition, cytoplasmic phase separations of these proteins containing intrinsically disordered low complexity regions into stress granules could be the stepping stone towards the formation of aggregates and also microtubule-related axonal transport could be involved in this process. Using iPSCs-derived motor neurons and patient material, we will investigate these processes concentrating on FUS, TDP-43 and dipeptide repeat proteins (DPRs) translated from the hexanucleotide repeats in C9ORF72.

Keywords:ALS

Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing