In vitro treatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation

Tiziana Bachetti, Eleonora Di Zanni, Pietro Balbi, Paola Bocca, Ignazia Prigione, Giovanni A. Deiana, Antonella Rezzani, Isabella Ceccherini, GianPietro Sechi

Research output: Contribution to journalArticlepeer-review

Abstract

Alexander disease is a rare, untreatable and usually fatal neurodegenerative disorder caused by heterozygous mutations of the glial fibrillary acidic protein (GFAP) gene which ultimately lead to formation of aggregates, containing also ?B-Crystallin, HSP27, ubiquitin and proteasome components. Recent findings indicate that up-regulation of ?B-Crystallin in mice carrying GFAP mutations may temper the pathogenesis of the disease. Neuroprotective effects of ceftriaxone have been reported in various animal models and, noteworthy, we have recently shown that the chronic use of ceftriaxone in a patient affected by an adult form of Alexander disease could halt its progression and ameliorate some of the symptoms. Here we show that ceftriaxone is able to reduce the intracytoplasmic aggregates of mutant GFAP in a cellular model of Alexander disease. Underlying mechanisms include mutant GFAP elimination, concurrent with up-regulation of HSP27 and ?B-Crystallin, polyubiquitination and autophagy. Ceftriaxone has also been shown to modulate the proteasome system, thus decreasing NF-?B activation and GFAP promoter transcriptional regulation, which further accounts for the down-modulation of GFAP protein levels. These mechanisms provide previously unknown neuroprotective targets of ceftriaxone and confirm its potential therapeutic role in patients with Alexander disease and other neurodegenerative disorders with astrocyte involvement.

Original languageEnglish
Pages (from-to)2152-2165
Number of pages14
JournalExperimental Cell Research
Volume316
Issue number13
DOIs
Publication statusPublished - Aug 2010

Keywords

  • Alexander disease
  • Ceftriaxone
  • Glial fibrillary acidic protein
  • Small heat shock proteins
  • Transcriptional regulation
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Cell Biology

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