Glial fibrillary acidic protein filaments can tolerate the incorporation of assembly-compromised GFAP-delta, but with consequences for filament organization and alphaB-crystallin association.

[alexander disease]

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 (approximately 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 (approximately 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 , R 416 W 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 alphaB-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 .

Diseases
Validation

Diseases presenting "increased association of alphab-crystallin with the intermediate filament" symptom

alexander disease

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