Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis

• Main Authors: Riccardo De Santis, Vincenzo Alfano, Valeria de Turris, Alessio Colantoni, Laura Santini, Maria Giovanna Garone, Giuseppe Antonacci, Giovanna Peruzzi, Emma Sudria-Lopez, Emanuel Wyler, Jasper J. Anink, Eleonora Aronica, Markus Landthaler, R. Jeroen Pasterkamp, Irene Bozzoni, Alessandro Rosa
• Format: Article
• Language: English
• Published: Elsevier 2019-06-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719307247

Summary: 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. : De Santis et al. show that the mutant RNA-binding protein FUS, linked to amyotrophic lateral sclerosis (ALS), targets other RNA-binding proteins, such as ELAVL4, in human motor neurons. This triggers aberrant crosstalk between mutant FUS and ELAVL4, which is found in pathological inclusions of ALS patients’ motor neurons. Keywords: FUS, ELAVL4, HuD, amytrophic lateral sclerosis, motor neuron, PAR-CLIP, TDP-43, stress granules, RNA-binding protein, Brillouin