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

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

• Authors: Tiziana Bachetti, Eleonora Di Zanni, Pietro Balbi, Paola Bocca, Ignazia Prigione, Giovanni A Deiana, Antonella Rezzani, Isabella Ceccherini, GianPietro Sechi
• Journal: Experimental cell research (Exp Cell Res) Vol. 316 Issue 13 Pg. 2152-65 (Aug 01 2010) ISSN: 1090-2422 [Electronic] United States
• PMID: 20471977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Glial Fibrillary Acidic Protein
• HSP27 Heat-Shock Proteins
• Mutant Proteins
• RNA, Messenger
• Ubiquitin
• alpha-Crystallin B Chain
• Ceftriaxone
• Luciferases
• Proteasome Endopeptidase Complex

Topics

• Anti-Bacterial Agents (pharmacology)
• Astrocytoma (drug therapy, metabolism)
• Autophagy
• Blotting, Western
• Brain Neoplasms (drug therapy, metabolism)
• Ceftriaxone (pharmacology)
• Cell Proliferation
• Fluorescent Antibody Technique
• Gene Expression Regulation (drug effects)
• Glial Fibrillary Acidic Protein (genetics, metabolism)
• HSP27 Heat-Shock Proteins (genetics, metabolism)
• Humans
• In Vitro Techniques
• Luciferases (metabolism)
• Mutant Proteins (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Proteasome Endopeptidase Complex (drug effects)
• Protein Multimerization
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured (drug effects, metabolism)
• Ubiquitin (metabolism)
• alpha-Crystallin B Chain (genetics, metabolism)