Troost D.: Ubiquinated RNA binding proteins in ALS

Our goal is to understand the pathological mechansisms leading to neurodegeneration and cell death in amyotrophic lateral sclerosis (ALS). The p62 protein (SQSTM1) discovered in 1986 appeared to be a so-called ubiquitin-binding scaffold protein that colocalizes with ubiquitinated protein aggregates in ALS. However, p62 is probably more than just a scaffold and involved in signalling, receptor internalization and protein turnover. In 2006 the RNA-binding protein TDP-43 was identified as pathological protein in the majority of fronto-temporal dementia (FTD) and most ALS cases. A second RNA-binding protein named FUS/TLS plays another important role in the pathogenesis of a subset of FTD and ALS. With antibodies to TDP-43, FUS and p62 we try to elucidate the borderline between normal and abnormal tissue in sporadic ALS, familial ALS, atypical cases of ALS and various forms of dementing neurodegenerative diseases not being classified. Since there is strong evidence that alterations in RNA processing might be a key event in the pathogenesis of these type of conditions we try to understand the relation between RNA-binding proteins and the development of inclusion body formation. This
includes mainly neuropathological and immunohistochemical studies on human postmortem brain and spinal cord tissues.