Beneficial effects of curcumin on GFAP filament organization and down-regulation of GFAP expression in an in vitro model of Alexander disease.

[alexander disease]

Heterozygous mutations of the GFAP gene are responsible for Alexander disease , a neurodegenerative disorder characterized by intracytoplasmic Rosenthal fibers (RFs ) in dystrophic astrocytes . In vivo and in vitro models have shown co -localization of mutant GFAP proteins with the small heat shock proteins (sHSPs ) HSP 27 and alphaB-crystallin , ubiquitin and proteasome components . Results reported by several recent studies agree on ascribing an altered cytoskeletal pattern to mutant GFAP proteins , an effect which induces mutant proteins accumulation , leading to impaired proteasome function and autophagy induction . On the basis of the protective role shown by both these small heat shock proteins (sHSPs ), and on the already well established neuroprotective effects of curcumin in several diseases , we have investigated the effects of this compound in an in vitro model of Alexander disease , consisting in U 251 -MG astrocytoma cells transiently transfected with a construct encoding for GFAP carrying the p .R 239 C mutation in frame with the reporter green fluorescent protein (GFP ). In particular , depending on the dose used , we have observed that curcumin is able to induce both HSP 27 and alphaB-crystallin , to reduce expression of both RNA and protein of endogenous GFAP , to induce autophagy and , finally , to rescue the filamentous organization of the GFAP mutant protein , thus suggesting a role of this spice in counteracting the pathogenic effects of GFAP mutations .

Diseases
Validation

Diseases presenting "p.r239c mutation in frame" symptom

alexander disease

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