Glial fibrillary acidic protein: Difference between revisions

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'''Glial fibrillary acidic protein''' ('''GFAP''') is a [[protein]] that is encoded by the ''GFAP'' [[gene]] in humans.<ref name="pmid9693047">{{cite journal | vauthors = Isaacs A, Baker M, Wavrant-De Vrièze F, Hutton M | title = Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17 | journal = Genomics | volume = 51 | issue = 1 | pages = 152–4 | date = Jul 1998 | pmid = 9693047 | doi = 10.1006/geno.1998.5360 }}</ref>
'''Glial fibrillary acidic protein''' ('''GFAP''') is a [[protein]] that is encoded by the ''GFAP'' [[gene]] in humans.<ref name="pmid9693047">{{cite journal | vauthors = Isaacs A, Baker M, Wavrant-De Vrièze F, Hutton M | title = Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17 | journal = Genomics | volume = 51 | issue = 1 | pages = 152–4 | date = Jul 1998 | pmid = 9693047 | doi = 10.1006/geno.1998.5360 }}</ref>


Glial fibrillary acidic protein is an [[intermediate filament]] (IF) protein that is expressed by numerous cell types of the [[central nervous system]] (CNS) including [[astrocyte]]s<ref name="pmid624958">{{cite journal | vauthors = Jacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA | title = Determination of glial fibrillary acidic protein (GFAP) in human brain tumors | journal = Journal of the Neurological Sciences | volume = 35 | issue = 1 | pages = 147–55 | date = Jan 1978 | pmid = 624958 | doi = 10.1016/0022-510x(78)90107-7 }}</ref> and [[ependymal cell]]s.<ref>{{cite journal | vauthors = Roessmann U, Velasco ME, Sindely SD, Gambetti P | title = Glial fibrillary acidic protein (GFAP) in ependymal cells during development. An immunocytochemical study | journal = Brain Research | volume = 200 | issue = 1 | pages = 13–21 | date = Oct 1980 | pmid = 6998542 | doi = 10.1016/0006-8993(80)91090-2 }}</ref> GFAP has also been found to be expressed in [[glomeruli]] and peritubular fibroblasts taken from rat kidneys<ref>{{cite journal | vauthors = Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H | title = The immunoreactivity of glial fibrillary acidic protein in mesangial cells and podocytes of the glomeruli of rat kidney in vivo and in culture | journal = Biology of the Cell / Under the Auspices of the European Cell Biology Organization | volume = 90 | issue = 1 | pages = 53–61 | date = Jan 1998 | pmid = 9691426 | doi = 10.1016/s0248-4900(98)80232-3 }}</ref> [[Leydig cell]]s of the testis in both hamsters<ref>{{cite journal | vauthors = Maunoury R, Portier MM, Léonard N, McCormick D | title = Glial fibrillary acidic protein immunoreactivity in adrenocortical and Leydig cells of the Syrian golden hamster (Mesocricetus auratus) | journal = Journal of Neuroimmunology | volume = 35 | issue = 1-3 | pages = 119–29 | date = Dec 1991 | pmid = 1720132 | doi=10.1016/0165-5728(91)90167-6}}</ref> and humans,<ref>{{cite journal | vauthors = Davidoff MS, Middendorff R, Köfüncü E, Müller D, Jezek D, Holstein AF | title = Leydig cells of the human testis possess astrocyte and oligodendrocyte marker molecules | journal = Acta Histochemica | volume = 104 | issue = 1 | pages = 39–49 | year = 2002 | pmid = 11993850 | doi = 10.1078/0065-1281-00630 }}</ref> human [[keratinocyte]]s,<ref>{{cite journal | vauthors = von Koskull H | title = Rapid identification of glial cells in human amniotic fluid with indirect immunofluorescence | journal = Acta Cytologica | volume = 28 | issue = 4 | pages = 393–400 | year = 1984 | pmid = 6205529 }}</ref> human [[osteocyte]]s and [[chondrocyte]]s<ref>{{cite journal | vauthors = Kasantikul V, Shuangshoti S | title = Positivity to glial fibrillary acidic protein in bone, cartilage, and chordoma | journal = Journal of Surgical Oncology | volume = 41 | issue = 1 | pages = 22–6 | date = May 1989 | pmid = 2654484 | doi = 10.1002/jso.2930410109 }}</ref> and stellate cells of the [[pancreatic stellate cell|pancreas]] and [[hepatic stellate cell|liver]] in rats.<ref>{{cite journal | vauthors = Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS | title = Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture | journal = Gut | volume = 43 | issue = 1 | pages = 128–33 | date = Jul 1998 | pmid = 9771417 | pmc = 1727174 | doi = 10.1136/gut.43.1.128 }}</ref> First described in 1971,<ref name="r2">{{cite journal | vauthors = Fuchs E, Weber K | title = Intermediate filaments: structure, dynamics, function, and disease | journal = Annual Review of Biochemistry | volume = 63 | issue = | pages = 345–82 | year = 1994 | pmid = 7979242 | doi = 10.1146/annurev.bi.63.070194.002021 }}</ref> GFAP is a type III IF protein that maps, in humans, to '''17q21'''.<ref name="pmid1847665">{{cite journal | vauthors = Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, 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 Research | volume = 51 | issue = 5 | pages = 1553–60 | date = Mar 1991 | pmid = 1847665 | doi = }}</ref> 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]],<ref>{{cite journal | vauthors = Cullen DK, Simon CM, LaPlaca MC | title = Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal-astrocytic co-cultures | journal = Brain Research | volume = 1158 | pages = 103–15 | date = Jul 2007 | pmid = 17555726 | pmc = 3179863 | doi = 10.1016/j.brainres.2007.04.070 }}</ref> 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.<ref name="pmid11059815">{{cite journal | vauthors = Eng LF, Ghirnikar RS, Lee YL | title = Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000) | journal = Neurochemical Research | volume = 25 | issue = 9-10 | pages = 1439–51 | date = Oct 2000 | pmid = 11059815 | doi = 10.1023/A:1007677003387 }}</ref>
Glial fibrillary acidic protein is an [[intermediate filament]] (IF) protein that is expressed by numerous cell types of the [[central nervous system]] (CNS) including [[astrocyte]]s<ref name="pmid624958">{{cite journal | vauthors = Jacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA | title = Determination of glial fibrillary acidic protein (GFAP) in human brain tumors | journal = Journal of the Neurological Sciences | volume = 35 | issue = 1 | pages = 147–55 | date = Jan 1978 | pmid = 624958 | doi = 10.1016/0022-510x(78)90107-7 }}</ref> and [[ependymal cell]]s during development.<ref>{{cite journal | vauthors = Roessmann U, Velasco ME, Sindely SD, Gambetti P | title = Glial fibrillary acidic protein (GFAP) in ependymal cells during development. An immunocytochemical study | journal = Brain Research | volume = 200 | issue = 1 | pages = 13–21 | date = Oct 1980 | pmid = 6998542 | doi = 10.1016/0006-8993(80)91090-2 }}</ref> GFAP has also been found to be expressed in [[glomeruli]] and peritubular fibroblasts taken from rat kidneys<ref>{{cite journal | vauthors = Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H | title = The immunoreactivity of glial fibrillary acidic protein in mesangial cells and podocytes of the glomeruli of rat kidney in vivo and in culture | journal = Biology of the Cell / Under the Auspices of the European Cell Biology Organization | volume = 90 | issue = 1 | pages = 53–61 | date = Jan 1998 | pmid = 9691426 | doi = 10.1016/s0248-4900(98)80232-3 }}</ref> [[Leydig cell]]s of the testis in both hamsters<ref>{{cite journal | vauthors = Maunoury R, Portier MM, Léonard N, McCormick D | title = Glial fibrillary acidic protein immunoreactivity in adrenocortical and Leydig cells of the Syrian golden hamster (Mesocricetus auratus) | journal = Journal of Neuroimmunology | volume = 35 | issue = 1-3 | pages = 119–29 | date = Dec 1991 | pmid = 1720132 | doi=10.1016/0165-5728(91)90167-6}}</ref> and humans,<ref>{{cite journal | vauthors = Davidoff MS, Middendorff R, Köfüncü E, Müller D, Jezek D, Holstein AF | title = Leydig cells of the human testis possess astrocyte and oligodendrocyte marker molecules | journal = Acta Histochemica | volume = 104 | issue = 1 | pages = 39–49 | year = 2002 | pmid = 11993850 | doi = 10.1078/0065-1281-00630 }}</ref> human [[keratinocyte]]s,<ref>{{cite journal | vauthors = von Koskull H | title = Rapid identification of glial cells in human amniotic fluid with indirect immunofluorescence | journal = Acta Cytologica | volume = 28 | issue = 4 | pages = 393–400 | year = 1984 | pmid = 6205529 }}</ref> human [[osteocyte]]s and [[chondrocyte]]s<ref>{{cite journal | vauthors = Kasantikul V, Shuangshoti S | title = Positivity to glial fibrillary acidic protein in bone, cartilage, and chordoma | journal = Journal of Surgical Oncology | volume = 41 | issue = 1 | pages = 22–6 | date = May 1989 | pmid = 2654484 | doi = 10.1002/jso.2930410109 }}</ref> and stellate cells of the [[pancreatic stellate cell|pancreas]] and [[hepatic stellate cell|liver]] in rats.<ref>{{cite journal | vauthors = Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS | title = Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture | journal = Gut | volume = 43 | issue = 1 | pages = 128–33 | date = Jul 1998 | pmid = 9771417 | pmc = 1727174 | doi = 10.1136/gut.43.1.128 }}</ref> First described in 1971,<ref name="r2">{{cite journal | vauthors = Fuchs E, Weber K | title = Intermediate filaments: structure, dynamics, function, and disease | journal = Annual Review of Biochemistry | volume = 63 | issue = | pages = 345–82 | year = 1994 | pmid = 7979242 | doi = 10.1146/annurev.bi.63.070194.002021 }}</ref> GFAP is a type III [[IF (protein)|IF protein]] that maps, in humans, to '''17q21'''.<ref name="pmid1847665">{{cite journal | vauthors = Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, 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 Research | volume = 51 | issue = 5 | pages = 1553–60 | date = Mar 1991 | pmid = 1847665 | doi = }}</ref> It is closely related to its non-[[Epithelium|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]],<ref>{{cite journal | vauthors = Cullen DK, Simon CM, LaPlaca MC | title = Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal-astrocytic co-cultures | journal = Brain Research | volume = 1158 | pages = 103–15 | date = Jul 2007 | pmid = 17555726 | pmc = 3179863 | doi = 10.1016/j.brainres.2007.04.070 }}</ref> 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.<ref name="pmid11059815">{{cite journal | vauthors = Eng LF, Ghirnikar RS, Lee YL | title = Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000) | journal = Neurochemical Research | volume = 25 | issue = 9-10 | pages = 1439–51 | date = Oct 2000 | pmid = 11059815 | doi = 10.1023/A:1007677003387 }}</ref>


==Structure==
==Structure==
Type III intermediate filaments contain three domains, named the head, rod and tail domains. The specific [[deoxyribonucleic acid|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 [[protein dimer|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).<ref name="r3">{{cite journal | vauthors = Reeves SA, Helman LJ, Allison A, Israel MA | title = Molecular cloning and primary structure of human glial fibrillary acidic protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 13 | pages = 5178–82 | date = Jul 1989 | pmid = 2740350 | pmc = 297581 | doi = 10.1073/pnas.86.13.5178 }}</ref> Interestingly, GFAP and other type III IF proteins cannot assemble with [[keratins]], the type I and II [[intermediate filament]]s: in cells that express both proteins, two separate intermediate filament networks form,<ref>{{cite journal | vauthors = McCormick MB, Coulombe PA, Fuchs E | title = Sorting out IF networks: consequences of domain swapping on IF recognition and assembly | journal = The Journal of Cell Biology | volume = 113 | issue = 5 | pages = 1111–24 | date = Jun 1991 | pmid = 1710225 | pmc = 2289006 | doi=10.1083/jcb.113.5.1111}}</ref> which can allow for specialization and increased variability.  
Type III [[Intermediate filament|intermediate filaments]] contain three domains, named the head, rod and tail domains. The specific [[deoxyribonucleic acid|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 [[protein dimer|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 [[Polymerization|polymerize]] with other type III proteins.<ref name="r3">{{cite journal | vauthors = Reeves SA, Helman LJ, Allison A, Israel MA | title = Molecular cloning and primary structure of human glial fibrillary acidic protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 13 | pages = 5178–82 | date = Jul 1989 | pmid = 2740350 | pmc = 297581 | doi = 10.1073/pnas.86.13.5178 }}</ref> GFAP and other type III IF proteins cannot assemble with [[keratins]], the type I and II [[intermediate filament]]s: in cells that express both proteins, two separate intermediate filament networks form,<ref>{{cite journal | vauthors = McCormick MB, Coulombe PA, Fuchs E | title = Sorting out IF networks: consequences of domain swapping on IF recognition and assembly | journal = The Journal of Cell Biology | volume = 113 | issue = 5 | pages = 1111–24 | date = Jun 1991 | pmid = 1710225 | pmc = 2289006 | doi=10.1083/jcb.113.5.1111}}</ref> which can allow for specialization and increased variability.  


To form networks, the initial GFAP dimers combine to make staggered [[tetrameric protein|tetramer]]s,<ref>{{cite journal | vauthors = Stewart M, Quinlan RA, Moir RD | title = 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 | journal = The Journal of Cell Biology | volume = 109 | issue = 1 | pages = 225–34 | date = Jul 1989 | pmid = 2745549 | pmc = 2115473 | doi = 10.1083/jcb.109.1.225 }}</ref> 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.<ref name="r3"/> 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 [[arginine]]s and an [[aromatic]] residue that have been shown to be required for proper assembly.<ref name="r2"/>
To form networks, the initial GFAP dimers combine to make staggered [[tetrameric protein|tetramer]]s,<ref>{{cite journal | vauthors = Stewart M, Quinlan RA, Moir RD | title = 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 | journal = The Journal of Cell Biology | volume = 109 | issue = 1 | pages = 225–34 | date = Jul 1989 | pmid = 2745549 | pmc = 2115473 | doi = 10.1083/jcb.109.1.225 }}</ref> 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.<ref name="r3"/> 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 [[arginine]]s and an [[aromatic]] residue that have been shown to be required for proper assembly.<ref name="r2"/>


==Function in the central nervous system==
==Function in the central nervous system==
GFAP is expressed in the [[central nervous system]] in astrocyte cells.<ref name="pmid624958"/><ref name="pmid24005729">{{cite journal | vauthors = Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV | title = In vitro differentiation of cultured human CD34+ cells into astrocytes | journal = Neurology India | volume = 61 | issue = 4 | pages = 383–8 | year = 2013 | pmid = 24005729 | doi = 10.4103/0028-3886.117615 }}</ref>  It is involved in many important CNS processes, including cell communication and the functioning of the [[blood brain barrier]].
GFAP is expressed in the [[central nervous system]] in astrocyte cells.<ref name="pmid624958"/><ref name="pmid24005729">{{cite journal | vauthors = Venkatesh K, Srikanth L, Vengamma B, Chandrasekhar C, Sanjeevkumar A, Mouleshwara Prasad BC, Sarma PV | title = In vitro differentiation of cultured human CD34+ cells into astrocytes | journal = Neurology India | volume = 61 | issue = 4 | pages = 383–8 | year = 2013 | pmid = 24005729 | doi = 10.4103/0028-3886.117615 }}</ref>  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.<ref name="pmid2165732">{{cite journal | vauthors = 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 = Advances in Experimental Medicine and Biology | volume = 265 | issue = | pages = 41–52 | year = 1990 | pmid = 2165732 | doi = 10.1007/978-1-4757-5876-4_4 }}</ref> 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]].<ref>{{cite journal | vauthors = 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 | date = Oct 1996 | pmid = 8893019 | doi = 10.1016/S0896-6273(00)80194-4 }}</ref> These data suggest that GFAP is necessary for many critical roles in the CNS.
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.<ref name="pmid2165732">{{cite journal | vauthors = 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 = Advances in Experimental Medicine and Biology | volume = 265 | issue = | pages = 41–52 | year = 1990 | pmid = 2165732 | doi = 10.1007/978-1-4757-5876-4_4 }}</ref> There are different sets of kinases at work; [[cdc2]] [[kinase]] acts only at the [[G2 phase]] transition, while other GFAP [[Kinase|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 mouse|knockout mice]] undergo multiple degenerative processes including abnormal [[myelination]], white matter structure deterioration, and functional/structural impairment of the [[blood–brain barrier]].<ref>{{cite journal | vauthors = 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 | date = Oct 1996 | pmid = 8893019 | doi = 10.1016/S0896-6273(00)80194-4 }}</ref> These data suggest that GFAP is necessary for many critical roles in the [[Central nervous system|CNS]].


GFAP is proposed to play a role in astrocyte-neuron interactions as well as [[cell signaling|cell-cell communication]]. In vitro, using [[antisense RNA]], astrocytes lacking GFAP do not form the extensions usually present with neurons.<ref>{{cite journal | vauthors = Weinstein DE, Shelanski ML, Liem RK | title = Suppression by antisense mRNA demonstrates a requirement for the glial fibrillary acidic protein in the formation of stable astrocytic processes in response to neurons | journal = The Journal of Cell Biology | volume = 112 | issue = 6 | pages = 1205–13 | date = Mar 1991 | pmid = 1999469 | pmc = 2288905 | doi = 10.1083/jcb.112.6.1205 }}</ref> 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.<ref name="r7">{{OMIM|137780|Glial Fibrillary Acidic Protein, GFAP}}</ref> Biochemical studies of GFAP have shown MgCl<sub>2</sub> and/or calcium/calmodulin dependent phosphorylation at various serine or threonine residues by [[protein kinase C|PKC]] and [[protein kinase A|PKA]]<ref>{{cite journal | vauthors = Harrison BC, Mobley PL | title = Phosphorylation of glial fibrillary acidic protein and vimentin by cytoskeletal-associated intermediate filament protein kinase activity in astrocytes | journal = Journal of Neurochemistry | volume = 58 | issue = 1 | pages = 320–7 | date = Jan 1992 | pmid = 1727439 | doi = 10.1111/j.1471-4159.1992.tb09313.x }}</ref> which are two [[protein kinase|kinase]]s that are important for the cytoplasmic transduction of signals. These data highlight the importance of GFAP for cell-cell communication.
GFAP is proposed to play a role in [[astrocyte]]-[[neuron]] interactions as well as [[cell signaling|cell-cell communication]]. [[In vitro]], using [[antisense RNA]], astrocytes lacking GFAP do not form the extensions usually present with neurons.<ref>{{cite journal | vauthors = Weinstein DE, Shelanski ML, Liem RK | title = Suppression by antisense mRNA demonstrates a requirement for the glial fibrillary acidic protein in the formation of stable astrocytic processes in response to neurons | journal = The Journal of Cell Biology | volume = 112 | issue = 6 | pages = 1205–13 | date = Mar 1991 | pmid = 1999469 | pmc = 2288905 | doi = 10.1083/jcb.112.6.1205 }}</ref> 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.<ref name="r7">{{OMIM|137780|Glial Fibrillary Acidic Protein, GFAP}}</ref> Biochemical studies of GFAP have shown [[MgCl2|MgCl<sub>2</sub>]] and/or [[calcium]]/[[calmodulin]] dependent [[phosphorylation]] at various serine or [[threonine]] residues by [[protein kinase C|PKC]] and [[protein kinase A|PKA]]<ref>{{cite journal | vauthors = Harrison BC, Mobley PL | title = Phosphorylation of glial fibrillary acidic protein and vimentin by cytoskeletal-associated intermediate filament protein kinase activity in astrocytes | journal = Journal of Neurochemistry | volume = 58 | issue = 1 | pages = 320–7 | date = Jan 1992 | pmid = 1727439 | doi = 10.1111/j.1471-4159.1992.tb09313.x }}</ref> which are two [[protein kinase|kinase]]s that are important for the [[Cytoplasm|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 scar]]s in a multitude of locations throughout the CNS including the eye<ref>{{cite journal | vauthors = Tuccari G, Trombetta C, Giardinelli MM, Arena F, Barresi G | title = Distribution of glial fibrillary acidic protein in normal and gliotic human retina | journal = Basic and Applied Histochemistry | volume = 30 | issue = 4 | pages = 425–32 | year = 1986 | pmid = 3548695 }}</ref> and brain.<ref>{{cite journal | vauthors = Paetau A, Elovaara I, Paasivuo R, Virtanen I, Palo J, Haltia M | title = Glial filaments are a major brain fraction in infantile neuronal ceroid-lipofuscinosis | journal = Acta Neuropathologica | volume = 65 | issue = 3-4 | pages = 190–94 | year = 1985 | pmid = 4038838 | doi = 10.1007/bf00686997 }}</ref>
GFAP has also been shown to be important in repair after CNS injury. More specifically for its role in the formation of [[glial scar]]s in a multitude of locations throughout the CNS including the [[eye]]<ref>{{cite journal | vauthors = Tuccari G, Trombetta C, Giardinelli MM, Arena F, Barresi G | title = Distribution of glial fibrillary acidic protein in normal and gliotic human retina | journal = Basic and Applied Histochemistry | volume = 30 | issue = 4 | pages = 425–32 | year = 1986 | pmid = 3548695 }}</ref> and [[brain]].<ref>{{cite journal | vauthors = Paetau A, Elovaara I, Paasivuo R, Virtanen I, Palo J, Haltia M | title = Glial filaments are a major brain fraction in infantile neuronal ceroid-lipofuscinosis | journal = Acta Neuropathologica | volume = 65 | issue = 3-4 | pages = 190–94 | year = 1985 | pmid = 4038838 | doi = 10.1007/bf00686997 }}</ref>


In 2016 a CNS inflammatory disorder associated with anti-GFAP antibodies was described. Patients with GFAP astrocytopathy developed meningoencephalomyelitis with inflammation of the meninges, the brain parenchyma, and the spinal cord. About one third of cases were associated with various cancers and many also expressed other CNS autoantibodies.
In 2016 a CNS inflammatory disorder associated with anti-GFAP [[Antibody|antibodies]] was described. Patients with GFAP [[astrocytopathy]] developed meningoencephalomyelitis with inflammation of the [[meninges]], the brain [[parenchyma]], and the [[spinal cord]]. About one third of cases were associated with various [[Cancer|cancers]] and many also expressed other CNS [[autoantibodies]].


==Disease states==
==Disease states==
[[Image:Anaplastic astrocytoma - gfap - very high mag.jpg|thumb|right|GFAP [[immunostain]]ing in a glial neoplasm ([[anaplastic astrocytoma]]).]]
[[Image:Anaplastic astrocytoma - gfap - very high mag.jpg|thumb|right|GFAP [[immunostain]]ing 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<ref>{{cite journal | vauthors = Bunge MB, Bunge RP, Ris H | title = Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord | journal = The Journal of Biophysical and Biochemical Cytology | volume = 10 | issue = 1 | pages = 67–94 | date = May 1961 | pmid = 13688845 | pmc = 2225064 | doi = 10.1083/jcb.10.1.67 }}</ref> and is partially caused by up-regulation of GFAP.<ref>{{cite journal | vauthors = Smith ME, Eng LF | title = Glial fibrillary acidic protein in chronic relapsing experimental allergic encephalomyelitis in SJL/J mice | journal = Journal of Neuroscience Research | volume = 18 | issue = 1 | pages = 203–8 | year = 1987 | pmid = 3682026 | doi = 10.1002/jnr.490180129 }}</ref>
There are multiple disorders associated with improper GFAP regulation, and injury can cause [[Glial Cells|glial cells]] to react in detrimental ways. [[Glial scarring]] is a consequence of several [[Neurodegeneration|neurodegenerative]] conditions, as well as injury that severs neural material. The scar is formed by [[Astrocyte|astrocytes]] interacting with [[fibrous tissue]] to re-establish the glial margins around the central injury core<ref>{{cite journal | vauthors = Bunge MB, Bunge RP, Ris H | title = Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord | journal = The Journal of Biophysical and Biochemical Cytology | volume = 10 | issue = 1 | pages = 67–94 | date = May 1961 | pmid = 13688845 | pmc = 2225064 | doi = 10.1083/jcb.10.1.67 }}</ref> and is partially caused by [[up-regulation]] of GFAP.<ref>{{cite journal | vauthors = Smith ME, Eng LF | title = Glial fibrillary acidic protein in chronic relapsing experimental allergic encephalomyelitis in SJL/J mice | journal = Journal of Neuroscience Research | volume = 18 | issue = 1 | pages = 203–8 | year = 1987 | pmid = 3682026 | doi = 10.1002/jnr.490180129 }}</ref>


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.<ref name="r9">{{cite web | url = http://healthlink.mcw.edu/article/921383447.html | title = Alexander Disease | author = HealthLink | date = 2007-11-25 | publisher = Medical College of Wisconsin}}</ref> The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as [[Rosenthal fiber]]s.<ref>{{cite journal | vauthors = Hagemann TL, Connor JX, Messing A | title = Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response | journal = The Journal of Neuroscience | volume = 26 | issue = 43 | pages = 11162–73 | date = Oct 2006 | pmid = 17065456 | pmc = | doi = 10.1523/JNEUROSCI.3260-06.2006 }}</ref> Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.<ref name="pmid11138011">{{cite journal | vauthors = 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 = Nature Genetics | volume = 27 | issue = 1 | pages = 117–20 | date = Jan 2001 | pmid = 11138011 | doi = 10.1038/83679 }}</ref> Some of these mutations have been proposed to be detrimental to cytoskeleton formation as well as an increase in [[caspase 3]] activity,<ref>{{cite journal | vauthors = Chen YS, Lim SC, Chen MH, Quinlan RA, Perng MD | title = 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 | journal = Experimental Cell Research | volume = 317 | issue = 16 | pages = 2252–66 | date = Oct 2011 | pmid = 21756903 | pmc = | doi = 10.1016/j.yexcr.2011.06.017 }}</ref> which would lead to increased [[apoptosis]] of cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.  
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 [[Epileptic seizure|seizures]].<ref name="r9">{{cite web | url = http://healthlink.mcw.edu/article/921383447.html | title = Alexander Disease | author = HealthLink | date = 2007-11-25 | publisher = Medical College of Wisconsin}}</ref> The cellular mechanism of the disease is the presence of [[Cytoplasm|cytoplasmic]] accumulations containing GFAP and [[Heat shock protein|heat shock proteins]], known as [[Rosenthal fiber]]s.<ref>{{cite journal | vauthors = Hagemann TL, Connor JX, Messing A | title = Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response | journal = The Journal of Neuroscience | volume = 26 | issue = 43 | pages = 11162–73 | date = Oct 2006 | pmid = 17065456 | pmc = | doi = 10.1523/JNEUROSCI.3260-06.2006 }}</ref> Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.<ref name="pmid11138011">{{cite journal | vauthors = 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 = Nature Genetics | volume = 27 | issue = 1 | pages = 117–20 | date = Jan 2001 | pmid = 11138011 | doi = 10.1038/83679 }}</ref> Some of these mutations have been proposed to be detrimental to [[cytoskeleton]] formation as well as an increase in [[caspase 3]] activity,<ref>{{cite journal | vauthors = Chen YS, Lim SC, Chen MH, Quinlan RA, Perng MD | title = 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 | journal = Experimental Cell Research | volume = 317 | issue = 16 | pages = 2252–66 | date = Oct 2011 | pmid = 21756903 | pmc = 4308095| doi = 10.1016/j.yexcr.2011.06.017 }}</ref> 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 (medicine)|acute]] infection or [[neurodegeneration]].<ref name =" Johnston-Wilson"/>
Notably, the expression of some GFAP [[isoforms]] have been reported to decrease in response to [[Acute (medicine)|acute]] infection or [[neurodegeneration]].<ref name ="Johnston-Wilson"/>
Additionally, reduction in GFAP expression has also been reported in [[Wernicke's encephalopathy]].<ref>{{cite journal | vauthors = Cullen KM, Halliday GM | title = Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon | journal = Alcohol and Alcoholism | volume = 2 | pages = 253–7 | year = 1994 | pmid = 8974344 }}</ref> The [[HIV-1]] viral envelope glycoprotein [[gp120]] can directly inhibit the phosphorylation of GFAP and GFAP levels can be decreased in response to [[Chronic (medical)|chronic]] infection with HIV-1,<ref>{{cite journal | vauthors = Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C | title = Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 4 | pages = 1541–5 | date = Feb 1993 | pmid = 8381971 | pmc = 45910 | doi = 10.1073/pnas.90.4.1541 }}</ref> [[varicella zoster]],<ref>{{cite journal | vauthors = Kennedy PG, Major EO, Williams RK, Straus SE | title = Down-regulation of glial fibrillary acidic protein expression during acute lytic varicella-zoster virus infection of cultured human astrocytes | journal = Virology | volume = 205 | issue = 2 | pages = 558–62 | date = Dec 1994 | pmid = 7975257 | pmc = | doi = 10.1006/viro.1994.1679 }}</ref> and [[pseudorabies]].<ref>{{cite journal | vauthors = Rinaman L, Card JP, Enquist LW | title = Spatiotemporal responses of astrocytes, ramified microglia, and brain macrophages to central neuronal infection with pseudorabies virus | journal = The Journal of Neuroscience | volume = 13 | issue = 2 | pages = 685–702 | date = Feb 1993 | pmid = 8381171 }}</ref> Decreases in GFAP expression have been reported in [[Down's syndrome]], [[schizophrenia]], [[bipolar disorder]] and [[Depression (mood)|depression]].<ref name=" Johnston-Wilson">{{cite journal | vauthors = 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 = Molecular Psychiatry | volume = 5 | issue = 2 | pages = 142–9 | date = Mar 2000 | pmid = 10822341 | doi = 10.1038/sj.mp.4000696 | url = http://www.nature.com/mp/journal/v5/n2/full/4000696a.html }}</ref>
Additionally, reduction in GFAP expression has also been reported in [[Wernicke's encephalopathy]].<ref>{{cite journal | vauthors = Cullen KM, Halliday GM | title = Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon | journal = Alcohol and Alcoholism | volume = 2 | pages = 253–7 | year = 1994 | pmid = 8974344 }}</ref> The [[HIV-1]] [[viral envelope]] [[glycoprotein]] [[gp120]] can directly inhibit the [[phosphorylation]] of GFAP and GFAP levels can be decreased in response to [[Chronic (medical)|chronic]] infection with HIV-1,<ref>{{cite journal | vauthors = Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C | title = Human immunodeficiency virus coat protein gp120 inhibits the beta-adrenergic regulation of astroglial and microglial functions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 4 | pages = 1541–5 | date = Feb 1993 | pmid = 8381971 | pmc = 45910 | doi = 10.1073/pnas.90.4.1541 }}</ref> [[varicella zoster]],<ref>{{cite journal | vauthors = Kennedy PG, Major EO, Williams RK, Straus SE | title = Down-regulation of glial fibrillary acidic protein expression during acute lytic varicella-zoster virus infection of cultured human astrocytes | journal = Virology | volume = 205 | issue = 2 | pages = 558–62 | date = Dec 1994 | pmid = 7975257 | pmc = | doi = 10.1006/viro.1994.1679 }}</ref> and [[pseudorabies]].<ref>{{cite journal | vauthors = Rinaman L, Card JP, Enquist LW | title = Spatiotemporal responses of astrocytes, ramified microglia, and brain macrophages to central neuronal infection with pseudorabies virus | journal = The Journal of Neuroscience | volume = 13 | issue = 2 | pages = 685–702 | date = Feb 1993 | pmid = 8381171 }}</ref> Decreases in GFAP expression have been reported in [[Down's syndrome]], [[schizophrenia]], [[bipolar disorder]] and [[Depression (mood)|depression]].<ref name=" Johnston-Wilson">{{cite journal | vauthors = 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 = Molecular Psychiatry | volume = 5 | issue = 2 | pages = 142–9 | date = Mar 2000 | pmid = 10822341 | doi = 10.1038/sj.mp.4000696 | url = http://www.nature.com/mp/journal/v5/n2/full/4000696a.html }}</ref>


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.<ref name="JHU_ECMO">{{cite web|title=Protein Found to Predict Brain Injury in Children on ECMO Life Support|url=http://www.hopkinschildrens.org/Protein-Found-to-Predict-Brain-Injury-in-Children-on-ECMO-Life-Support.aspx|publisher=[[Johns Hopkins Children's Center]]|accessdate=11 December 2010|date=19 November 2010}}</ref> GFAP levels are already used as a marker of neurologic damage in adults who suffer [[stroke]]s and traumatic brain injuries.<ref name="JHU_ECMO" />
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.<ref name="JHU_ECMO">{{cite web|title=Protein Found to Predict Brain Injury in Children on ECMO Life Support|url=http://www.hopkinschildrens.org/Protein-Found-to-Predict-Brain-Injury-in-Children-on-ECMO-Life-Support.aspx|publisher=[[Johns Hopkins Children's Center]]|accessdate=11 December 2010|date=19 November 2010}}</ref> GFAP levels are already used as a marker of neurologic damage in adults who suffer [[stroke]]s and traumatic brain injuries.<ref name="JHU_ECMO" />
Line 36: Line 36:


==Isoforms==
==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.<ref name="pmid21219963">{{cite journal | vauthors = Middeldorp J, Hol EM | title = GFAP in health and disease | journal = Progress in Neurobiology | volume = 93 | issue = 3 | pages = 421–43 | date = Mar 2011 | pmid = 21219963 | doi = 10.1016/j.pneurobio.2011.01.005 }}</ref>
Although GFAP alpha is the only isoform which is able to assemble homomerically, GFAP has 8 different [[isoforms]] which label distinct subpopulations of [[Astrocyte|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 cell|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 [[Morphology (biology)|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 [[Alzheimer's disease|AD]] [[pathology]].<ref name="pmid21219963">{{cite journal | vauthors = Middeldorp J, Hol EM | title = GFAP in health and disease | journal = Progress in Neurobiology | volume = 93 | issue = 3 | pages = 421–43 | date = Mar 2011 | pmid = 21219963 | doi = 10.1016/j.pneurobio.2011.01.005 }}</ref>


== See also ==
== See also ==
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== References ==
== References ==
{{Reflist|33em}}
{{Reflist|32em}}
 
== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Cáceres-Marzal C, Vaquerizo J, Galán E, Fernández S | title = Early mitochondrial dysfunction in an infant with Alexander disease | journal = Pediatric Neurology | volume = 35 | issue = 4 | pages = 293–6 | date = October 2006 | pmid = 16996408 | doi = 10.1016/j.pediatrneurol.2006.03.010 }}
{{refend}}


== External links ==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1172/  GeneReviews/NCBI/NIH/UW entry on Alexander disease]
* [https://www.ncbi.nlm.nih.gov/books/NBK1172/  GeneReviews/NCBI/NIH/UW entry on Alexander disease]
* [https://www.ncbi.nlm.nih.gov/omim/137780,203450,137780,203450 OMIM entries on Alexander disease]
* [https://www.ncbi.nlm.nih.gov/omim/137780,203450,137780,203450 OMIM entries on Alexander disease]
* {{MeshName|Glial+Fibrillary+Acidic+Protein|3=Glial Fibrillary Acidic Protein}}
* {{MeshName|Glial+Fibrillary+Acidic+Protein|3=Glial Fibrillary Acidic Protein}}


{{Cytoskeletal Proteins}}
{{Cytoskeletal Proteins}}
{{Portal bar|Mitochondria|Gene Wiki|border=no}}


[[Category:Proteins]]
[[Category:Proteins]]
[[Category:Biology of bipolar disorder]]
[[Category:Biology of bipolar disorder]]

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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 during development.[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.[14] 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]

In 2016 a CNS inflammatory disorder associated with anti-GFAP antibodies was described. Patients with GFAP astrocytopathy developed meningoencephalomyelitis with inflammation of the meninges, the brain parenchyma, and the spinal cord. About one third of cases were associated with various cancers and many also expressed other CNS autoantibodies.

Disease states

File:Anaplastic astrocytoma - gfap - very high mag.jpg
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. ↑ 2.0 2.1 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. ↑ 10.0 10.1 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. ↑ 14.0 14.1 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.
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  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
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  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.
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  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. PMC 4308095. PMID 21756903.
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  36. ↑ 36.0 36.1 "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.

Further reading

External links

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