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

Cell Rep. 2019 Jun 25;27(13):3818-3831.e5. doi: 10.1016/j.celrep.2019.05.085.


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.

Keywords: Brillouin; ELAVL4; FUS; HuD; PAR-CLIP; RNA-binding protein; TDP-43; amytrophic lateral sclerosis; motor neuron; stress granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Cytoplasm / genetics
  • Cytoplasm / metabolism*
  • Cytoplasm / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • ELAV-Like Protein 4 / genetics
  • ELAV-Like Protein 4 / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Mutation*
  • Oxidative Stress / genetics
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*


  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • ELAV-Like Protein 4
  • ELAVL4 protein, human
  • FUS protein, human
  • RNA-Binding Protein FUS
  • TARDBP protein, human