Ablation of p2X7 receptor exacerbates gliosis and motoneuron death in the SOD1-G93A mouse model of amyotrophic lateral sclerosis

Savina Apolloni, Susanna Amadio, Cinzia Montilli, Cinzia Volonté, Nadia D'ambrosi

Research output: Contribution to journalArticlepeer-review


Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motoneurons. The primary triggers for motoneuron degeneration are stillunknown, but inflammationis considered an important contributing factor. P2X7 receptor is a key player in microglia response to toxic insults and was previously shown to increase pro-inflammatory actions of SOD1-G93A ALS microglia. We therefore hypothesized that lack of P2X7 receptor could modify disease features in the SOD1-G93A mice. Hetero- and homozygous P2X7 receptor knock-out SOD1-G93A mice were thus generated and analysed for body weight, disease onset and progression (by behavioural scores, grip and rotarod tests) and survival. Although the lifespan of P2X7+/- and P2X7-/-/SOD1-G93A female mice was extended by 6-7% with respect to SOD1-G93Amice, to our surprise the clinical onset was significantly anticipated and the disease progression worsened in both male and female P2X7-/-/SOD1-G93A mice. Consistently, we found increased astrogliosis, microgliosis, motoneuron loss, induction of the pro-inflammatory markers NOX2 and iNOS and activation of the MAPKs pathway in the lumbar spinal cord of end-stage P2X7-/-/SOD1-G93A mice. These results show that the constitutive deletion of P2X7 receptor aggravates the ALS pathogenesis, suggesting that the receptor might have beneficial effects in at least definite stages of the disease. This study unravels a complex dual role of P2X7 receptor inALSand strengthens the importance of a successful timewindow of therapeutic intervention in contrasting the pathology.

Original languageEnglish
Article numberddt259
Pages (from-to)4102-4116
Number of pages15
JournalHuman Molecular Genetics
Issue number20
Publication statusPublished - Oct 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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