Glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is an
intermediate filament(IF) proteinthat is found in glial cellssuch as astrocytes, but also in other cell types such as Leydig cellsin the testis and stellate cells in the liver.cite journal | author = J A Holash, S I Harik, G Perry, and P A Stewart| title = Barrier properties of testis microvessels. | journal = Proc Natl Acad Sci USA | volume = 90| issue = | pages = 11069–11073| year = 1993 | pmid = 7902579 | doi = 10.1073/pnas.90.23.11069 ] First described in 1971,cite journal | author = Fuchs E, Weber K | title = Intermediate filaments: structure, dynamics, function, and disease | journal = Annu. Rev. Biochem. | volume = 63 | issue = | pages = 345–82 | year = 1994 | pmid = 7979242 | doi = 10.1146/annurev.bi.63.070194.002021 ] GFAP is a type III IF protein that maps, in humans, to 17q21.cite journal | author = Bongcam-Rudloff, E.; Nister, M.; Betsholtz, C.; Wang, J.-L.; Stenman, G.; Huebner, K.; Croce, C. M.; Westermark, B. | title = Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes| journal = Cancer Res. | volume = 51 | pages = 1553–60| year = 1991 | pmid = 1847665 ] It is closely related to its non-epithelial family members, vimentin, desmin, and peripherin, which are all involved in the structure and function of the cell’s cytoskeleton. GFAP is thought to help to maintain astrocyte mechanical strength, as well as the shape of cells but its exact function remains poorly understood, despite the number of studies using it as a cell marker.
Type III intermediate filaments contain three domains, the most conserved of which is the rod domain. The specific
DNAsequence for this region of the protein may differ between the different intermediate filament genes for type III proteins, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a dimer, with the N-terminaland C-terminalof each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with neurofilamentprotein (NF-L).cite journal | author = Reeves SA, Helman LJ, Allison A, Israel MA | title = Molecular cloning and primary structure of human glial fibrillary acidic protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 13 | pages = 5178–82 | year = 1989 | pmid = 2740350 | doi = 10.1073/pnas.86.13.5178 ] Interestingly, GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filaments. In cells that express both proteins, two separate intermediate filament networks form, which can allow for specialization and increased variability.
To form networks, the initial dimers combine to make staggered
tetramers, which are the basic subunits of an intermediate filament. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation. The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two arginines and an aromaticresidue that have been shown to be required for proper assembly. The sizes of the head and tail regions are quite different between GFAP and its more common counterpart vimentin, which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network.
The amount of GFAP the cell produces is regulated by numerous methods, such as
cytokineand hormonepresence. Increased expression of this protein is evident in different situations, commonly referred to as "Astrocytic activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma (tumor) cell lines, but not in mature astroctyes. This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually.
In mature cells, the most studied avenue of change in filament amount is the
phosphorylationof GFAP, which can occur at five different sites on the protein.cite journal | author = Inagaki M, Gonda Y, Nishizawa K, Kitamura S, Sato C, Ando S, Tanabe K, Kikuchi K, Tsuiki S, Nishi Y | title = Phosphorylation sites linked to glial filament disassembly in vitro locate in a non-alpha-helical head domain | journal = J. Biol. Chem. | volume = 265 | issue = 8 | pages = 4722–9 | year = 1990 | pmid = 2155236 | doi = | issn = | url = http://www.jbc.org/cgi/content/abstract/265/8/4722 | format = abstract ] This post-translational modification occurs at the head domain and alters the charge of the protein, resulting in disaggregation and subsequent break down of the filaments. The relationship between the level of filamentous GFAP present is usually in a stable equilibrium with free protein, and currently the functional importance of the alteration in the levels of GFAP is not fully understood.
GFAP is expressed in the
central nervous systemin astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, cell communication, and the functioning of the blood brain barrier.
GFAP has been shown to play a role in
mitosisby adjusting the filament network present in the cell. During mitosis, there is an increase in the amount of phosphorylated GFAP, and a movement of this modified protein to the cleavage furrow.cite journal | author = Tardy M, Fages C, Le Prince G, Rolland B, Nunez J | title = Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes | journal = Adv. Exp. Med. Biol. | volume = 265 | issue = | pages = 41–52 | year = 1990 | pmid = 2165732 | doi = | issn = ] There are different sets of kinases at work; cdc2 kinaseacts only at the G2 phasetransition, while other GFAP kinases are active at the cleavage furrow alone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. In mature cells, many GFAP functions have been discovered using GFAP knockout mice. These knockout micelack intermediate filaments in the hippocampusand in the white matterof the spinal cord. Research also shows that in older mice there is a degeneration of multiple astrocyte functions; the myelination becomes abnormal, white matter structure deteriorates, and there are noticeable changes to the blood-brain barrier.cite journal | author = Goss JR, Finch CE, Morgan DG | title = Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain | journal = Neurobiol. Aging | volume = 12 | issue = 2 | pages = 165–70 | year = 1991 | pmid = 2052130 | doi = 10.1016/0197-4580(91)90056-P ] Therefore, GFAP is believed to be involved in the long term upkeep of normal CNS myelination.
GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using
antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons. Research also shows that Purkinje cellsin GFAP knockout mice do not exhibit normal structure, and these mice have deficits in some conditioning experiments, such as eye-blink tasks.OMIM|137780|Glial Fibrillary Acidic Protein, GFAP] Therefore, GFAP is thought to play an important role in the maintenance of Purkinje cell communication, and possibly many other neural cell types.
There are multiple disorders associated with improper GFAP regulation, and injury can cause glial cells to react in detrimental ways.
Glial scarringis a consequence of several neurodegenerative conditions, as well as injury that severs neural material. The scar is formed by astrocytes interacting with fibrous tissue to re-establish the glia margins around the central tissue core,cite journal | author = Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS | title = GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination | journal = Neuron | volume = 17 | issue = 4 | pages = 607–15 | year = 1996 | pmid = 8893019 | doi = 10.1016/S0896-6273(00)80194-4 ] and is caused by up-regulation of GFAP. The scar acts as a barrier to neuronal growth, and prevents neural regeneration.
Another condition directly related to GFAP is
Alexander disease. This disease is a rare genetic disorder, which affects mostly males, that alters the growth of the myelin sheath. Its symptoms include: mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures.cite web | url = http://healthlink.mcw.edu/article/921383447.html | title = Alexander Disease | author = HealthLink | date = 2007-11-25 | publisher = Medical College of Wisconsin] The cellular trait is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers.
The relationship between GFAP and Alexander disease is not completely understood, but mutations in the coding region of the GFAP gene are associated with the presence of this condition.cite journal | author = Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A | title = Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease | journal = Nat. Genet. | volume = 27 | issue = 1 | pages = 117–20 | year = 2001 | pmid = 11138011 | doi = 10.1038/83679 ] These mutations are proposed to act in a gain of function manner, as the knockout GFAP phenotype does not resemble the cytoplasmic GFAP mass. The relationship between the Rosenthal fibers and the observable phenotypes is believed to be due to interference in astrocyte interactions with other cells, and a possible inability to maintain the blood brain barrier.
GFAP is reported to increase dramatically in response to acute infection or
GFAP can be
phosphorylatedat five sites (Thr7, Ser8, Ser13, Ser17 and Ser38) in response to numerous stimuli. The expression of some GFAP isoformsare decreased in response to tumour necrosis factor-alpha, basic fibroblast growth factor, and glucocorticoidsin cell cultures. The HIV-1viral envelope glycoprotein gp120can directly inhibit the phosphorylation of GFAP and GFAP levels can be decreased in response to chronic infection with HIV-1, varicella zoster, and pseudorabies. GFAP decreases have been reported in Down's syndrome, schizophrenia, bipolar disorderand depression.cite journal | author = Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH | title = Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium | journal = Mol. Psychiatry | volume = 5 | issue = 2 | pages = 142–9 | year = 2000 | pmid = 10822341 | doi = 10.1038/sj.mp.4000696| url = http://www.nature.com/mp/journal/v5/n2/full/4000696a.html ]
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