Beneficial effects of curcumin on GFAP filament organization and down-regulation of GFAP expression in an in vitro model of 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) HSP27 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 U251-MG astrocytoma cells transiently transfected with a construct encoding for GFAP carrying the p.R239C 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 HSP27 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.
Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5, 16148 Genova, Italy.
Tiziana
T
Bachetti
Eleonora
E
Di Zanni
Pietro
P
Balbi
Roberto
R
Ravazzolo
GianPietro
G
Sechi
Isabella
I
Ceccherini
D038261:Alexander Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
C059215:CRYAB protein, human; D017931:DNA Primers; D005904:Glial Fibrillary Acidic Protein; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D038203:alpha-Crystallin B Chain; D003474:Curcumin