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Intermediate filament transcription in astrocytes is repressed by proteasome inhibition

Jinte Middeldorp^*, Willem Kamphuis^*, Jacqueline A. Sluijs^*, Dalila Achoui^*, Cathalijn H. C. Leenaars^*, Matthijs G. P. Feenstra^*, Paula van Tijn^*,1, David F. Fischer, Celia Berkers, Huib Ovaa, Roy A. Quinlan and Elly M. Hol^*,2

^* Department of Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands;

BioFocus DPI, Leiden, The Netherlands;

Division of Cellular Biochemistry, Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; and

School of Biological and Biomedical Sciences, Durham University, Durham, UK

² Correspondence: Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. E-mail: e.hol{at}nin.knaw.nl

Increased expression of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) is a characteristic of astrogliosis. This process occurs in the brain during aging and neurodegeneration and coincides with impairment of the ubiquitin proteasome system. Inhibition of the proteasome impairs protein degradation; therefore, we hypothesized that the increase in GFAP may be the result of impaired proteasomal activity in astrocytes. We investigated the effect of proteasome inhibitors on GFAP expression and other intermediate filament proteins in human astrocytoma cells and in a rat brain model for astrogliosis. Extensive quantitative RT-PCR, immunocytochemistry, and Western blot analysis resulted unexpectedly in a strong decrease of GFAP mRNA to <4% of control levels [Control (DMSO) 100±19.2%; proteasome inhibitor (epoxomicin) 3.5±1.3%, n=8; P0.001] and a loss of GFAP protein in astrocytes in vitro. We show that the proteasome alters GFAP promoter activity, possibly mediated by transcription factors as demonstrated by a GFAP promoter-luciferase assay and RT² Profiler PCR array for human transcription factors. Most important, we demonstrate that proteasome inhibitors also reduce GFAP and vimentin expression in a rat model for induced astrogliosis in vivo. Therefore, proteasome inhibitors could serve as a potential therapy to modulate astrogliosis associated with CNS injuries and disease.—Middeldorp, J., Kamphuis, W., Sluijs, J. A., Achoui, D., Leenaars, C. H. C., Feenstra, M. G. P., van Tijn, P., Fischer, D. F., Berkers, C., Ovaa, H., Quinlan, R. A., Hol, E. M. Intermediate filament transcription in astrocytes is repressed by proteasome inhibition.

Key Words: glial fibrillary acidic protein • astrogliosis • protein degradation • neurodegenerative diseases

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