Prof. Boris Rogelj
Dept. of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
Biomedical Research Institute BRIS, Ljubljana, Slovenia
Faculty of Pharmacy, University of Ljubljana, Slovenia
RNA binding proteins and protein binding RNAs in ALS and FTLD
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)
are devastating neurodegenerative diseases that form two ends of a complex disease
spectrum. Aggregation of RNA binding proteins TDP-43 and to a lesser extent FUS is
one of the hallmark pathological features of ALS and FTDL, and suggests
perturbance of the RNA metabolism in their aetiology. In 95% of all ALS and 60% of
FTLD patients the aggregating protein is TDP-43, thus defining the major part of the
disease spectrum as TDP-43 proteinopathies. However, only a very small percent of
aggregation is caused by TDP-43 mutations. ‘FUSopaties’ are less common with
mutant FUS aggregation associated with ~ 5% ALS and wildtype accumulation in 510% of FTLD. Functional and pathogenomic similarities between TDP-43 and FUS
point to a crucial pathogenic pathway potentially involving RNA processing and
transport. The disease importance of RNA related upstream processes has recently
been further substantiated with association of the GGGGCC expanded repeat
mutation in C9orf72 with ALS/FTLD. The main questions in the field are what makes
wild-type or mutated TDP-43 or FUS aggregate in ALS and FTLD and what is the
role of perturbed RNA metabolism in these diseases.