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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)4572
JournalSci. Rep.
Issue number1
Publication statusPublished - Mar 14 2019


Dive into the research topics of 'Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death'. Together they form a unique fingerprint.

Cite this