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

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. [Display omitted] •We report the RNA interactome of wild-type and mutant FUS in human motor neurons•Mutant FUS binds the mRNA 3′ UTR of other RNA-binding proteins, including ELAVL4•ELAVL4, expressed at increased levels, interacts with mutant FUS in the cytoplasm•ELAVL4 proteinopathy occurs in both FUS ALS and in sporadic ALS patients 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.