Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Research output: Contribution to journalArticle

Abstract

Mutations of Fused in sarcoma (FUS), a ribonucleoprotein involved in RNA metabolism, have been found associated with both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). Notably, besides mutations in the coding sequence, also mutations into the 3′ untranslated region, leading to increased levels of the wild-type protein, have been associated with neuronal death and ALS pathology, in ALS models and patients. The mechanistic link between altered FUS levels and ALS-related neurodegeneration is far to be elucidated, as well as the consequences of elevated FUS levels in the modulation of the inflammatory response sustained by glial cells, a well-recognized player in ALS progression. Here, we studied the effect of wild-type FUS overexpression on the responsiveness of mouse and human neural progenitor-derived astrocytes to a pro-inflammatory stimulus (IL1β) used to mimic an inflammatory environment. We found that astrocytes with increased FUS levels were more sensitive to IL1β, as shown by their enhanced expression of inflammatory genes, compared with control astrocytes. Moreover, astrocytes overexpressing FUS promoted neuronal cell death and pro-inflammatory microglia activation. We conclude that overexpression of wild-type FUS intrinsically affects astrocyte reactivity and drives their properties toward pro-inflammatory and neurotoxic functions, suggesting that a non-cell autonomous mechanism can support neurodegeneration in FUS-mutated animals and patients.

Details

Authors
  • Maria Antonietta Ajmone-Cat
  • Angela Onori
  • Camilla Toselli
  • Eleonora Stronati
  • Mariangela Morlando
  • Irene Bozzoni
  • Emanuela Monni
  • Zaal Kokaia
  • Giuseppe Lupo
  • Luisa Minghetti
  • Stefano Biagioni
  • Emanuele Cacci
Organisations
External organisations
  • Istituto Superiore di Sanità
  • Sapienza University of Rome
  • Italian Institute of Technology
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Neurosciences
Original languageEnglish
Article number4572
JournalScientific Reports
Volume9
Issue number1
Publication statusPublished - 2019 Mar 14
Publication categoryResearch
Peer-reviewedYes