Glial fibrillary acidic protein

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Glial fibrillary acidic protein
Identifiers
Symbols GFAP ; FLJ42474; FLJ45472
External IDs OMIM137780 MGI95697 HomoloGene1554 GeneCards: GFAP Gene
RNA expression pattern
PBB GE GFAP 203540 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2670 14580
Ensembl ENSG00000131095 ENSMUSG00000020932
UniProt P14136 P03995
RefSeq (mRNA) NM_001131019 NM_001131020
RefSeq (protein) NP_001124491 NP_001124492
Location (UCSC) Chr 17:
42.98 – 42.99 Mb
Chr 11:
102.89 – 102.9 Mb
PubMed search [1] [2]

Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the GFAP gene in humans .[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. Glial fibrillary acidic protein (GFAP) was named and first isolated and characterized by Lawrence F. Eng in 1969.[13]

Structure[edit]

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).[14] 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,[15] which can allow for specialization and increased variability.

To form networks, the initial GFAP dimers combine to make staggered tetramers,[16] 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.[14] 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[edit]

GFAP is expressed in the central nervous system in astrocyte cells.[2][17] 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.[18] 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.[19] 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.[20] 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.[21] Biochemical studies of GFAP have shown MgCl2 and/or calcium/calmodulin dependent phosphorylation at various serine or threonine residues by PKC and PKA[22] 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[23] and brain.[24]

Disease states[edit]

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[25] and is partially caused by up-regulation of GFAP.[26]

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.[27] The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers.[28] Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.[29] Some of these mutations have been proposed to be detrimental to cytoskeleton formation as well as an increase in caspase 3 activity,[30] 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.[31] Additionally, reduction in GFAP expression has also been reported in Wernicke's encephalopathy.[32] 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,[33] varicella zoster,[34] and pseudorabies.[35] Decreases in GFAP expression have been reported in Down's syndrome, schizophrenia, bipolar disorder and depression.[31]

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.[36] GFAP levels are already used as a marker of neurologic damage in adults who suffer strokes and traumatic brain injuries.[36]

Interactions[edit]

Glial fibrillary acidic protein has been shown to interact with MEN1[37] and PSEN1.[38]

Isoforms[edit]

Although GFAP alpha is the only isoform which is able to assemble homomerically, GFAP has 8 different isoforms which label distinct subpopulations of astrocytes in the human and rodent brain. These isoforms include GFAP kappa, GFAP +1 and the currently best researched GFAP delta. GFAP delta appears to be linked with neural stem cells (NSCs) and may be involved in migration. GFAP+1 is an antibody which labels two isoforms. Although GFAP+1 positive astrocytes are supposedly not reactive astrocytes, they have a wide variety of morphologies including processes of up to 0.95mm (seen in the human brain). The expression of GFAP+1 positive astrocytes is linked with old age and the onset of AD pathology.[39]

See also[edit]

References[edit]

  1. ^ Isaacs A, Baker M, Wavrant-De Vrièze F, Hutton M (July 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. 
  2. ^ a b Jacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA (January 1978). "Determination of glial fibrillary acidic protein (GFAP) in human brain tumors". J. Neurol. Sci. 35 (1): 147–55. doi:10.1016/0022-510x(78)90107-7. PMID 624958. 
  3. ^ Roessmann U, Velasco ME, Sindely SD, Gambetti P (1980). "Glial fibrillary acidic protein (GFAP) in ependymal cells during development. An immunocytochemical study". Brain Research 200 (1): 13–21. doi:10.1016/0006-8993(80)91090-2. PMID 6998542.  edit
  4. ^ Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H (1998). "The immunoreactivity of glial fibrillary acidic protein in mesangial cells and podocytes of the glomeruli of rat kidney in vivo and in culture". Biology of the cell / under the auspices of the European Cell Biology Organization 90 (1): 53–61. doi:10.1016/s0248-4900(98)80232-3. PMID 9691426.  edit
  5. ^ Maunoury R, Portier MM, Léonard N, McCormick D (1991). "Glial fibrillary acidic protein immunoreactivity in adrenocortical and Leydig cells of the Syrian golden hamster (Mesocricetus auratus)". Journal of neuroimmunology 35 (1–3): 119–129. PMID 1720132.  edit
  6. ^ Davidoff MS, Middendorff R, Köfüncü E, Müller D, Jezek D, Holstein AF (2002). "Leydig cells of the human testis possess astrocyte and oligodendrocyte marker molecules". Acta histochemica 104 (1): 39–49. doi:10.1078/0065-1281-00630. PMID 11993850.  edit
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  8. ^ Kasantikul V, Shuangshoti S (1989). "Positivity to glial fibrillary acidic protein in bone, cartilage, and chordoma". Journal of surgical oncology 41 (1): 22–26. doi:10.1002/jso.2930410109. PMID 2654484.  edit
  9. ^ Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS (1998). "Periacinar stellate shaped cells in rat pancreas: Identification, isolation, and culture". Gut 43 (1): 128–133. doi:10.1136/gut.43.1.128. PMC 1727174. PMID 9771417.  edit
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  11. ^ Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, Westermark B (March 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. 
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  13. ^ Eng LF, Ghirnikar RS, Lee YL (October 2000). "Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000)". Neurochem. Res. 25 (9-10): 1439–51. PMID 11059815. 
  14. ^ 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. 
  15. ^ McCormick MB, Coulombe PA, Fuchs E (1991). "Sorting out IF networks: Consequences of domain swapping on IF recognition and assembly". The Journal of Cell Bio 113 (5): 1111–1124. PMC 2289006. PMID 1710225.  edit
  16. ^ Stewart M, Quinlan RA, Moir RD (1989). "Molecular interactions in paracrystals of a fragment corresponding to the alpha-helical coiled-coil rod portion of glial fibrillary acidic protein: Evidence for an antiparallel packing of molecules and polymorphism related to intermediate filament structure". The Journal of Cell Biology 109 (1): 225–234. doi:10.1083/jcb.109.1.225. PMC 2115473. PMID 2745549.  edit
  17. ^ Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV (2013). "In vitro differentiation of cultured human CD34+ cells into astrocytes". Neurol India 61 (4): 383–8. doi:10.4103/0028-3886.117615. PMID 24005729. 
  18. ^ 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. doi:10.1007/978-1-4757-5876-4_4. PMID 2165732. 
  19. ^ Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS (1996). "GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination". Neuron 17 (4): 607–615. doi:10.1016/S0896-6273(00)80194-4. PMID 8893019.  edit
  20. ^ Weinstein DE, Shelanski ML, Liem RK (1991). "Suppression by antisense mRNA demonstrates a requirement for the glial fibrillary acidic protein in the formation of stable astrocytic processes in response to neurons". The Journal of Cell Biology 112 (6): 1205–1213. doi:10.1083/jcb.112.6.1205. PMC 2288905. PMID 1999469.  edit
  21. ^ Online 'Mendelian Inheritance in Man' (OMIM) Glial Fibrillary Acidic Protein, GFAP -137780
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  24. ^ Paetau A, Elovaara I, Paasivuo R, Virtanen I, Palo J, Haltia M (1985). "Glial filaments are a major brain fraction in infantile neuronal ceroid-lipofuscinosis". Acta Neuropathologica 65 (3–4): 190–194. doi:10.1007/bf00686997. PMID 4038838.  edit
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  36. ^ 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. 
  37. ^ Lopez-Egido J, Cunningham J, Berg M, Oberg K, Bongcam-Rudloff E, Gobl A (August 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): 175–83. doi:10.1006/excr.2002.5575. PMID 12169273. 
  38. ^ Nielsen AL, Holm IE, Johansen M, Bonven B, Jørgensen P, Jørgensen AL (August 2002). "A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins". J. Biol. Chem. 277 (33): 29983–91. doi:10.1074/jbc.M112121200. PMID 12058025. 
  39. ^ Middeldorp J, Hol EM (March 2011). "GFAP in health and disease". Prog. Neurobiol. 93 (3): 421–43. doi:10.1016/j.pneurobio.2011.01.005. PMID 21219963. 

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