Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis
55 Pages Posted: 8 Oct 2018 Publication Status: PublishedMore...
The motor neuron disease 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 induced Pluripotent Stem Cells (iPSC)-derived motor neurons (MNs). We show that, whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift towards 3’ untranslated regions (3’UTRs). The neural specific 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 ALS patients ELAVL4 represents a neural specific component of FUS-positive cytoplasmic aggregates. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.
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