Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in amyotrophic lateral sclerosis
Authors
- R. De Santis
- V. Alfano
- V. de Turris
- A. Colantoni
- L. Santini
- M.G. Garone
- G. Antonacci
- G. Peruzzi
- E. Sudria-Lopez
- E. Wyler
- J.J. Anink
- E. Aronica
- M. Landthaler
- R.J. Pasterkamp
- I. Bozzoni
- A. Rosa
Journal
- Cell Reports
Citation
- Cell Rep 27 (13): 3818-3831
Abstract
Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3′ UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.