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

Bachetti, Tiziana and Di Zanni, Eleonora and Balbi, Pietro and Bocca, Paola and Prigione, Ignazia and Deiana, Giovanni Andrea and Rezzani, Antonella and Ceccherini, Isabella and Sechi, Gianpietro (2010) In vitrotreatments with ceftriaxone promote elimination of mutant glial fibrillary acidic protein and transcription down-regulation. Experimental Cell Research, Vol. 316 (13), p. 2152-2165. eISSN 1090-2422. Article.

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DOI: 10.1016/j.yexcr.2010.05.005

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 αB-Crystallin, HSP27, ubiquitin and proteasome components. Recent findings indicate that up-regulation of αB-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 αB-Crystallin, polyubiquitination and autophagy. Ceftriaxone has also been shown to modulate the proteasome system, thus decreasing NF-κB 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.

Item Type:Article
ID Code:5596
Status:Published
Refereed:Yes
Uncontrolled Keywords:Alexander disease, ceftriaxone, glial fibrillary acidic protein, small heat shock proteins, ubiquitin-proteasome system, transcriptional regulation
Subjects:Area 06 - Scienze mediche > MED/05 Patologia clinica
Area 06 - Scienze mediche > MED/26 Neurologia
Divisions:001 Università di Sassari > 01 Dipartimenti > Neuroscienze, scienze materno infantili
Publisher:Academic Press / Elsevier
eISSN:1090-2422
Copyright Holders:© 2010 Elsevier
Deposited On:11 Mar 2011 10:47

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