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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-, but with Consequences for Filament Organization and B-Crystallin Association

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

*School of Biological and Biomedical Sciences, The University of Durham, Durham DH1 3LE, United Kingdom; and 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-, the most abundant isoform, and seven other differentially expressed transcripts including GFAP-. GFAP- has an altered C-terminal domain that renders it incapable of self-assembly in vitro. When titrated with GFAP-, assembly was restored providing GFAP- levels were kept low (10%). In a range of immortalized and transformed astrocyte derived cell lines and human spinal cord, we show that GFAP- 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- 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 B-crystallin with the intermediate filament fraction of transfected cells. These studies suggest that the major physiological role of the assembly-compromised GFAP- 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.

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

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