Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in amyotrophic lateral sclerosis

Autor/innen

  • 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

Quellenangabe

  • Cell Rep 27 (13): 3818-3831

Zusammenfassung

  • 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.


DOI

doi:10.1016/j.celrep.2019.05.085