Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm

Valeria Gerbino, Maria Teresa Carrì, Mauro Cozzolino, Tilmann Achsel

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Genes encoding RNA-binding proteins have frequently been implicated in various motor neuron diseases, but the particular step in RNA metabolism that is vulnerable in motor neurons remains unknown. FUS, a nuclear protein, forms cytoplasmic aggregates in cells affected by amyotrophic lateral sclerosis (ALS), and mutations disturbing the nuclear import of FUS cause the disease. It is extremely likely that the cytoplasmic aggregates are cytotoxic because they trap important factors; the nature of these factors, however, remains to be elucidated. Here we show that FUS associates in a neuronal cell line with SMN, the causative factor in spinal muscular atrophy (SMA). The two genes work on the same pathway, as FUS binds to spliceosomal snRNPs downstream of the SMN function. Pathogenic FUS mutations do not disturb snRNP binding. Instead, cytoplasmic mislocalisation of FUS causes partial mis-localisation of snRNAs to the cytoplasm, which in turn causes a change in the behaviour of the alternative splicing machinery. FUS, and especially its mutations, thus have a similar effect as SMN1 deletion in SMA, suggesting that motor neurons could indeed be particularly sensitive to changes in alternative splicing.

Original languageEnglish
Pages (from-to)120-128
Number of pages9
JournalNeurobiology of Disease
Volume55
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Spinal Muscular Atrophy
Cytoplasm
Alternative Splicing
Motor Neurons
Mutation
Small Nuclear Ribonucleoproteins
Motor Neuron Disease
RNA-Binding Proteins
Cell Nucleus Active Transport
Amyotrophic Lateral Sclerosis
Nuclear Proteins
Genes
RNA
Cell Line

Keywords

  • Amyotrophic lateral sclerosis
  • Fused in Sarcoma Protein (FUS)
  • Small nuclear RNA
  • Spinal muscular atrophy
  • Survival of Motor Neuron Protein (SMN)

ASJC Scopus subject areas

  • Neurology

Cite this

Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm. / Gerbino, Valeria; Carrì, Maria Teresa; Cozzolino, Mauro; Achsel, Tilmann.

In: Neurobiology of Disease, Vol. 55, 07.2013, p. 120-128.

Research output: Contribution to journalArticle

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