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Originally published as MBC in Press, 10.1091/mbc.E08-03-0284 on August 13, 2008 Originally published as MBC in Press, 10.1091/mbc.E08-03-0284 on August 6, 2008

Vol. 19, Issue 10, 4521-4533, October 2008

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Glial Fibrillary Acidic Protein Filaments Can Tolerate the Incorporation of Assembly-compromised GFAP-{delta}, but with Consequences for Filament Organization and {alpha}B-Crystallin Association

Ming-Der Perng*, Shu-Fang Wen*, Terry Gibbon*, Jinte Middeldorp{dagger}, Jacqueline Sluijs{dagger}, Elly M. Hol{dagger}, and Roy A. Quinlan*

*School of Biological and Biomedical Sciences, The University of Durham, Durham DH1 3LE, United Kingdom; and {dagger}Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands

Submitted March 14, 2008; Revised July 8, 2008; Accepted July 30, 2008
Monitoring Editor: Thomas D. Pollard

The glial fibrillary acidic protein (GFAP) gene is alternatively spliced to give GFAP-{alpha}, the most abundant isoform, and seven other differentially expressed transcripts including GFAP-{delta}. GFAP-{delta} has an altered C-terminal domain that renders it incapable of self-assembly in vitro. When titrated with GFAP-{alpha}, assembly was restored providing GFAP-{delta} levels were kept low (~10%). In a range of immortalized and transformed astrocyte derived cell lines and human spinal cord, we show that GFAP-{delta} is naturally part of the endogenous intermediate filaments, although levels were low (~10%). This suggests that GFAP filaments can naturally accommodate a small proportion of assembly-compromised partners. Indeed, two other assembly-compromised GFAP constructs, namely enhanced green fluorescent protein (eGFP)-tagged GFAP and the Alexander disease–causing GFAP mutant, R416W GFAP both showed similar in vitro assembly characteristics to GFAP-{delta} and could also be incorporated into endogenous filament networks in transfected cells, providing expression levels were kept low. Another common feature was the increased association of {alpha}B-crystallin with the intermediate filament fraction of transfected cells. These studies suggest that the major physiological role of the assembly-compromised GFAP-{delta} splice variant is as a modulator of the GFAP filament surface, effecting changes in both protein– and filament–filament associations as well as Jnk phosphorylation.


This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-03-0284) on August 13, 2008.

Address correspondence to: Roy A. Quinlan (r.a.quinlan{at}durham.ac.uk)




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