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

Ajmone-Cat, Maria Antonietta; Onori, Angela; Toselli, Camilla; Stronati, Eleonora; Morlando, Mariangela; Bozzoni, Irene; Monni, Emanuela LU ; Kokaia, Zaal LU ; Lupo, Giuseppe and Minghetti, Luisa, et al. (2019) In Scientific Reports 9(1).
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... (More)

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.

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Scientific Reports
volume
9
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85062953966
ISSN
2045-2322
DOI
10.1038/s41598-019-41040-4
language
English
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yes
id
90643203-66d2-40c7-91d0-64be930d6e19
date added to LUP
2019-03-27 12:16:18
date last changed
2019-06-27 03:00:21
@article{90643203-66d2-40c7-91d0-64be930d6e19,
  abstract     = {<p>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.</p>},
  articleno    = {4572},
  author       = {Ajmone-Cat, Maria Antonietta and Onori, Angela and Toselli, Camilla and Stronati, Eleonora and Morlando, Mariangela and Bozzoni, Irene and Monni, Emanuela and Kokaia, Zaal and Lupo, Giuseppe and Minghetti, Luisa and Biagioni, Stefano and Cacci, Emanuele},
  issn         = {2045-2322},
  language     = {eng},
  month        = {03},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death},
  url          = {http://dx.doi.org/10.1038/s41598-019-41040-4},
  volume       = {9},
  year         = {2019},
}