Glial fibrillary acidic protein

Glial fibrillary acidic protein
Identifiers
Symbols GFAP ; ALXDRD
External IDs OMIM: 137780 MGI: 95697 HomoloGene: 1554 GeneCards: GFAP Gene
RNA expression pattern
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:
44.91 – 44.92 Mb		 Chr 11:
102.89 – 102.9 Mb
PubMed search

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

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

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

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

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

Isoforms

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

References

  1. ↑ Isaacs A, Baker M, Wavrant-De Vrièze F, Hutton M (Jul 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. 1 2 Jacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA (Jan 1978). "Determination of glial fibrillary acidic protein (GFAP) in human brain tumors". Journal of the Neurological Sciences 35 (1): 147–55. doi:10.1016/0022-510x(78)90107-7. PMID 624958.
  3. ↑ Roessmann U, Velasco ME, Sindely SD, Gambetti P (Oct 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.
  4. ↑ Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H (Jan 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.
  5. ↑ Maunoury R, Portier MM, Léonard N, McCormick D (Dec 1991). "Glial fibrillary acidic protein immunoreactivity in adrenocortical and Leydig cells of the Syrian golden hamster (Mesocricetus auratus)". Journal of Neuroimmunology 35 (1-3): 119–29. doi:10.1016/0165-5728(91)90167-6. PMID 1720132.
  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.
  7. ↑ von Koskull H (1984). "Rapid identification of glial cells in human amniotic fluid with indirect immunofluorescence". Acta Cytologica 28 (4): 393–400. PMID 6205529.
  8. ↑ Kasantikul V, Shuangshoti S (May 1989). "Positivity to glial fibrillary acidic protein in bone, cartilage, and chordoma". Journal of Surgical Oncology 41 (1): 22–6. doi:10.1002/jso.2930410109. PMID 2654484.
  9. ↑ Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS (Jul 1998). "Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture". Gut 43 (1): 128–33. doi:10.1136/gut.43.1.128. PMC 1727174. PMID 9771417.
  10. 1 2 Fuchs E, Weber K (1994). "Intermediate filaments: structure, dynamics, function, and disease". Annual Review of Biochemistry 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 (Mar 1991). "Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes". Cancer Research 51 (5): 1553–60. PMID 1847665.
  12. ↑ Cullen DK, Simon CM, LaPlaca MC (Jul 2007). "Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal-astrocytic co-cultures". Brain Research 1158: 103–15. doi:10.1016/j.brainres.2007.04.070. PMC 3179863. PMID 17555726.
  13. ↑ Eng LF, Ghirnikar RS, Lee YL (Oct 2000). "Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000)". Neurochemical Research 25 (9-10): 1439–51. doi:10.1023/A:1007677003387. PMID 11059815.
  14. 1 2 Reeves SA, Helman LJ, Allison A, Israel MA (Jul 1989). "Molecular cloning and primary structure of human glial fibrillary acidic protein". Proceedings of the National Academy of Sciences of the United States of America 86 (13): 5178–82. doi:10.1073/pnas.86.13.5178. PMC 297581. PMID 2740350.
  15. ↑ McCormick MB, Coulombe PA, Fuchs E (Jun 1991). "Sorting out IF networks: consequences of domain swapping on IF recognition and assembly". The Journal of Cell Biology 113 (5): 1111–24. doi:10.1083/jcb.113.5.1111. PMC 2289006. PMID 1710225.
  16. ↑ Stewart M, Quinlan RA, Moir RD (Jul 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): 225–34. doi:10.1083/jcb.109.1.225. PMC 2115473. PMID 2745549.
  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". Neurology 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". Advances in Experimental Medicine and Biology 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 (Oct 1996). "GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination". Neuron 17 (4): 607–15. doi:10.1016/S0896-6273(00)80194-4. PMID 8893019.
  20. ↑ Weinstein DE, Shelanski ML, Liem RK (Mar 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): 1205–13. doi:10.1083/jcb.112.6.1205. PMC 2288905. PMID 1999469.
  21. ↑ Online 'Mendelian Inheritance in Man' (OMIM) Glial Fibrillary Acidic Protein, GFAP -137780
  22. ↑ Harrison BC, Mobley PL (Jan 1992). "Phosphorylation of glial fibrillary acidic protein and vimentin by cytoskeletal-associated intermediate filament protein kinase activity in astrocytes". Journal of Neurochemistry 58 (1): 320–7. doi:10.1111/j.1471-4159.1992.tb09313.x. PMID 1727439.
  23. ↑ Tuccari G, Trombetta C, Giardinelli MM, Arena F, Barresi G (1986). "Distribution of glial fibrillary acidic protein in normal and gliotic human retina". Basic and Applied Histochemistry 30 (4): 425–32. PMID 3548695.
  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): 190–94. doi:10.1007/bf00686997. PMID 4038838.
  25. ↑ Bunge MB, Bunge RP, Ris H (May 1961). "Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord". The Journal of Biophysical and Biochemical Cytology 10 (1): 67–94. doi:10.1083/jcb.10.1.67. PMC 2225064. PMID 13688845.
  26. ↑ Smith ME, Eng LF (1987). "Glial fibrillary acidic protein in chronic relapsing experimental allergic encephalomyelitis in SJL/J mice". Journal of Neuroscience Research 18 (1): 203–8. doi:10.1002/jnr.490180129. PMID 3682026.
  27. ↑ HealthLink (2007-11-25). "Alexander Disease". Medical College of Wisconsin.
  28. ↑ Hagemann TL, Connor JX, Messing A (Oct 2006). "Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response". The Journal of Neuroscience 26 (43): 11162–73. doi:10.1523/JNEUROSCI.3260-06.2006. PMID 17065456.
  29. ↑ Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (Jan 2001). "Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease". Nature Genetics 27 (1): 117–20. doi:10.1038/83679. PMID 11138011.
  30. ↑ Chen YS, Lim SC, Chen MH, Quinlan RA, Perng MD (Oct 2011). "Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability". Experimental Cell Research 317 (16): 2252–66. doi:10.1016/j.yexcr.2011.06.017. PMID 21756903.
  31. 1 2 Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (Mar 2000). "Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium". Molecular Psychiatry 5 (2): 142–9. doi:10.1038/sj.mp.4000696. PMID 10822341.
  32. ↑ Cullen KM, Halliday GM (1994). "Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon". Alcohol and Alcoholism 2: 253–7. PMID 8974344.
  33. ↑ Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C (Feb 1993). "Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions". Proceedings of the National Academy of Sciences of the United States of America 90 (4): 1541–5. doi:10.1073/pnas.90.4.1541. PMC 45910. PMID 8381971.
  34. ↑ Kennedy PG, Major EO, Williams RK, Straus SE (Dec 1994). "Down-regulation of glial fibrillary acidic protein expression during acute lytic varicella-zoster virus infection of cultured human astrocytes". Virology 205 (2): 558–62. doi:10.1006/viro.1994.1679. PMID 7975257.
  35. ↑ Rinaman L, Card JP, Enquist LW (Feb 1993). "Spatiotemporal responses of astrocytes, ramified microglia, and brain macrophages to central neuronal infection with pseudorabies virus". The Journal of Neuroscience 13 (2): 685–702. PMID 8381171.
  36. 1 2 "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 (Aug 2002). "Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity". Experimental Cell Research 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 (Aug 2002). "A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins". The Journal of Biological Chemistry 277 (33): 29983–91. doi:10.1074/jbc.M112121200. PMID 12058025.
  39. ↑ Middeldorp J, Hol EM (Mar 2011). "GFAP in health and disease". Progress in Neurobiology 93 (3): 421–43. doi:10.1016/j.pneurobio.2011.01.005. PMID 21219963.

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