GFAP: functional implications gleaned from studies of genetically engineered mice.

Albee Messing; Michael Brenner

doi:10.1002/glia.10219

Home/Archive/PubMed

PubMed · 12761871

GFAP: functional implications gleaned from studies of genetically engineered mice.

Albee Messing·Michael Brenner

View original source ↗Export metadata ↓

Abstract

GFAP is the major intermediate filament of mature astrocytes, and its relatively specific expression in these cells suggests an important function. To study the role of the GFAP gene, mice have been created carrying null alleles (no protein), modified alleles (altered protein), or added wild type alleles (elevated protein). Surprisingly, absence of GFAP has relatively subtle effects on development. On the other hand, over-expression can be lethal, and led to the discovery that GFAP coding mutations are responsible for most cases of Alexander disease, a devastating neurodegenerative disorder. Here we review what the various GFAP mouse models reveal about GFAP and astrocyte function.

Explore related subjects

Alexander Disease Animals Astrocytes Brain Disease Models, Animal Genetic Engineering Glial Fibrillary Acidic Protein Gliosis Intermediate Filaments Mice Mice, Transgenic Journal Article Research Support, U.S. Gov't, P.H.S.Review

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Albee Messing, Michael Brenner. 2003. GFAP: functional implications gleaned from studies of genetically engineered mice.. https://doi.org/10.1002/glia.10219

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2006

Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response.

Mutations in the gene for the astrocyte specific intermediate filament, glial fibrillary acidic protein (GFAP), cause the rare leukodystrophy Alexander disease (AxD). To study the pathology of this primary astrocyte defect, we have generated knock-in mice with missense mutations homologous to those found in humans. In this report, we show that mice with GFAP-R76H and -R236H mutations develop Rosenthal fibers, the hallmark protein aggregates observed in astrocytes in AxD, in the hippocampus, corpus callosum, olfactory bulbs, subpial, and periventricular regions. Astrocytes in these areas appear reactive and total GFAP expression is elevated. Although general white matter architecture and myelination appear normal, when crossed with an antioxidant response element reporter line, the mutant mice show a distinct pattern of reporter-gene induction that is especially prominent in the corpus callosum, and histochemical staining reveals accumulation of iron in the same region. The mutant mice have a normal lifespan and show no overt behavioral defects, but are more susceptible to kainate-induced seizures. Although these mice demonstrate increased GFAP expression by themselves, further elevation of GFAP via crosses to GFAP transgenic animals leads to a shift in GFAP solubility, an increased stress response, and ultimately death. The mice do not display the full spectrum of pathology observed in human infantile AxD, but may more closely resemble the adult form of the disease. These studies provide formal proof linking GFAP mutations with Rosenthal fibers and oxidative stress, and correlate gliosis and GFAP protein levels to the severity of the disease.

Alexander Disease↗

PubMed2006

Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease.

Protein aggregates in astrocytes that contain glial fibrillary acidic protein (GFAP), small heat shock proteins, and ubiquitinated proteins are termed Rosenthal fibers and characterize Alexander disease, a leukodystrophy caused by heterozygous mutations in GFAP. The mechanisms responsible for the massive accumulation of GFAP in Alexander disease remain unclear. In this study, we show that overexpression of both wild type and R239C mutant human GFAP led to cytoplasmic inclusions. GFAP accumulation also led to a decrease of proteasome activity and an activation of the MLK2-JNK pathway. In turn, the expression of activated mixed lineage kinases (MLKs) induced JNK activation and increased GFAP accumulation, whereas blocking the JNK pathway decreased GFAP accumulation. Activated MLK also inhibited proteasome function. A direct inhibition of proteasome function pharmacologically further activated JNK. Our data suggest a synergistic interplay between the proteasome and the SAPK/JNK pathway in the context of GFAP accumulation. Feedback interactions among GFAP accumulation, SAPK/JNK activation, and proteasomal hypofunction cooperate to produce further protein accumulation and cellular stress responses.

Alexander Disease↗

PubMed2006

Fluoro-Jade: new fluorescent marker of Rosenthal fibers.

Rosenthal fibers are homogeneous eosinophilic masses found in astrocytes that are composed of glial fibrillary acidic protein (GFAP) aggregates along with chaperone proteins and other unknown components. Rosenthal fiber formation is a pathological hallmark of Alexander disease and its detection is diagnostically significant. However, the lack of a specific fluorescent marker has greatly limited the histochemical characterization of Rosenthal fibers. Here, we report for the first time a fluorescent marker of Rosenthal fibers called Fluoro Jade. Fluoro Jade-positive masses were seen in samples of Alexander disease brain, pilocytic astrocytoma, and in brain tissue from a mouse model of Alexander disease. Fluoro Jade co-labeled tissue samples stained with GFAP immunofluorescence. Our results indicated that Fluoro Jade labeled Rosenthal fibers, and that Rosenthal fibers could be labeled with antibodies of interest in combination with Fluoro Jade staining.

Alexander Disease↗