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==Isoforms==
==Isoforms==
GFAP has 8 different isoforms which show differential expression in the human and rodent brain. New research is being conducted into determining the significance of such isoforms. The currently best researched isoform is GFAP delta which appears to be linked with neural stem cells (NSCs). GFAP+1 is an antibody which labels to isoforms whichare found in astrocytes with interesting morphology, only after development and in AD pathology.
GFAP has 8 different isoforms which show differential expression in the human and rodent brain. New research is being conducted into determining the significance of such isoforms. The currently best researched isoform is GFAP delta which appears to be linked with neural stem cells (NSCs). GFAP+1 is an antibody which labels two isoforms whichare found in astrocytes with interesting morphology, only after development and in AD pathology.


==Interactions==
==Interactions==

Revision as of 08:26, 5 December 2011

Template:PBB Glial fibrillary acidic protein (GFAP) is a protein that in humans is encoded by the GFAP gene.[1]

Glial fibrillary acidic protein is an intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS) including astrocytes, [2] and ependymal cells.[3] GFAP has also been found to be expressed in glomeruli and peritubular fibroblasts taken from rat kidneys[4] Leydig cells of the testis in both hamsters[5] and humans,[6] human keratinocytes,[7] human osteocytes and chondrocytes[8] and stellate cells of the pancreas and liver in rats.[9] First described in 1971,[10] GFAP is a type III IF protein that maps, in humans, to 17q21.[11] 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,[12] 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.

Structure

Type III intermediate filaments contain three domains, named the head, rod and tail domains. The specific DNA sequence for the rod domain may differ between different type III intermediate filaments, 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-terminal and C-terminal of 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 neurofilament protein (NF-L).[13] 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,[14] which can allow for specialization and increased variability.

To form networks, the initial GFAP dimers combine to make staggered tetramers,[15] which are the basic subunits of an intermediate filament. Since rod domains alone in vitro do not form filaments, the non-helical head and tail domains are necessary for filament formation.[13] The head and tail regions have greater variability of sequence and structure. In spite of this increased variability, the head of GFAP contains two conserved arginines and an aromatic residue that have been shown to be required for proper assembly.[10]

Function in the central nervous system

GFAP is expressed in the central nervous system in astrocyte cells.[16] It is involved in many important CNS processes, including cell communication and the functioning of the blood brain barrier.

GFAP has been shown to play a role in mitosis by 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.[17] There are different sets of kinases at work; cdc2 kinase acts only at the G2 phase transition, 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. Studies have also shown that GFAP knockout mice undergo multiple degenerative processes including abnormal myelination, white matter structure deterioration, and functional/structural impairment of the blood-brain barrier.[18] These data suggest that GFAP is necessary for many critical roles in the CNS.

GFAP is proposed to play a role in astrocyte-neuron interactions as well as cell-cell communication. In vitro, using antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons.[19] Studies have also shown that Purkinje cells in GFAP knockout mice do not exhibit normal structure, and these mice demonstrate deficits in conditioning experiments such as the eye-blink task.[20] Biochemical studies of GFAP have shown MgCl2 and/or calcium/calmodulin dependent phosphorylation at various serine or threonine residues by PKC and PKA[21] which are two kinases that are important for the cytoplasmic transduction of signals. These data highlight the importance of GFAP for cell-cell communication.

GFAP has also been shown to be important in repair after CNS injury. More specifically for its role in the formation of glial scars in a multitude of locations throughout the CNS including the eye[22] and brain.[23]

Disease states

GFAP immunostaining in a glial neoplasm (anaplastic astrocytoma).

There are multiple disorders associated with improper GFAP regulation, and injury can cause glial cells to react in detrimental ways. Glial scarring is 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 glial margins around the central injury core[24] and is partially caused by up-regulation of GFAP.[25]

Another condition directly related to GFAP is Alexander disease, a rare genetic disorder. Its symptoms include mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures.[26] The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers.[27] Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.[28] Some of these mutations have been proposed to be detrimental to cytoskeleton formation as well as an increase in caspase 3 activity,[29] which would lead to increased apoptosis of cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.

Notably, the expression of some GFAP isoforms have been reported to decrease in response to acute infection or neurodegeneration.[30] Additionally, reduction in GFAP expression has also been reported in Wernicke's encephalopathy.[31] The HIV-1 viral envelope glycoprotein gp120 can directly inhibit the phosphorylation of GFAP and GFAP levels can be decreased in response to chronic infection with HIV-1,[32] varicella zoster,[33] and pseudorabies.[34] Decreases in GFAP expression have been reported in Down's syndrome, schizophrenia, bipolar disorder and depression.[30]

In a study of 22 child patients undergoing extra-corporeal membrane oxygenation (ECMO), children with abnormally high levels of GFAP were 13 times more likely to die and 11 times more likely to suffer brain injury than children with normal GFAP levels.[35] GFAP levels are already used as a marker of neurologic damage in adults who suffer strokes and traumatic brain injuries.[35]

Isoforms

GFAP has 8 different isoforms which show differential expression in the human and rodent brain. New research is being conducted into determining the significance of such isoforms. The currently best researched isoform is GFAP delta which appears to be linked with neural stem cells (NSCs). GFAP+1 is an antibody which labels two isoforms whichare found in astrocytes with interesting morphology, only after development and in AD pathology.

Interactions

Glial fibrillary acidic protein has been shown to interact with MEN1[36] and PSEN1.[37]

See also

References

  1. ^ Isaacs A, Baker M, Wavrant-De Vrièze F, Hutton M (1998). "Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17". Genomics. 51 (1): 152–4. doi:10.1006/geno.1998.5360. PMID 9693047. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 624958, please use {{cite journal}} with |pmid=624958 instead.
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  9. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9771417, please use {{cite journal}} with |pmid=9771417 instead.
  10. ^ a b Fuchs E, Weber K (1994). "Intermediate filaments: structure, dynamics, function, and disease". Annu. Rev. Biochem. 63: 345–82. doi:10.1146/annurev.bi.63.070194.002021. PMID 7979242.
  11. ^ Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, Westermark B (1991). "Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes". Cancer Res. 51 (5): 1553–60. PMID 1847665. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17555726, please use {{cite journal}} with |pmid=17555726 instead.
  13. ^ a b Reeves SA, Helman LJ, Allison A, Israel MA (1989). "Molecular cloning and primary structure of human glial fibrillary acidic protein". Proc. Natl. Acad. Sci. U.S.A. 86 (13): 5178–82. doi:10.1073/pnas.86.13.5178. PMC 297581. PMID 2740350.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1710225, please use {{cite journal}} with |pmid=1710225 instead.
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  16. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 624958, please use {{cite journal}} with |pmid=624958 instead.
  17. ^ Tardy M, Fages C, Le Prince G, Rolland B, Nunez J (1990). "Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes". Adv. Exp. Med. Biol. 265: 41–52. PMID 2165732.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8893019, please use {{cite journal}} with |pmid=8893019 instead.
  19. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1999469, please use {{cite journal}} with |pmid=1999469 instead.
  20. ^ Online Mendelian Inheritance in Man (OMIM): Glial Fibrillary Acidic Protein, GFAP - 137780
  21. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 1727439, please use {{cite journal}} with |pmid=1727439 instead.
  22. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 3548695, please use {{cite journal}} with |pmid=3548695 instead.
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  25. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 3682026, please use {{cite journal}} with |pmid=3682026 instead.
  26. ^ HealthLink (2007-11-25). "Alexander Disease". Medical College of Wisconsin.
  27. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17065456, please use {{cite journal}} with |pmid=17065456 instead.
  28. ^ Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (2001). "Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease". Nat. Genet. 27 (1): 117–20. doi:10.1038/83679. PMID 11138011.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21756903, please use {{cite journal}} with |pmid=21756903 instead.
  30. ^ a b Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (2000). "Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium". Mol. Psychiatry. 5 (2): 142–9. doi:10.1038/sj.mp.4000696. PMID 10822341.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8974344, please use {{cite journal}} with |pmid=8974344 instead.
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  34. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 8381171, please use {{cite journal}} with |pmid=8381171 instead.
  35. ^ a b "Protein Found to Predict Brain Injury in Children on ECMO Life Support". Johns Hopkins Children's Center. 19 November 2010. Retrieved 11 December 2010.
  36. ^ Lopez-Egido, Juan (2002). "Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity". Exp. Cell Res. 278 (2). United States: 175–83. doi:10.1006/excr.2002.5575. ISSN 0014-4827. PMID 12169273. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  37. ^ Nielsen, Anders Lade (2002). "A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins". J. Biol. Chem. 277 (33). United States: 29983–91. doi:10.1074/jbc.M112121200. ISSN 0021-9258. PMID 12058025. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)

External Links

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