GFAP is closely related to the other three non-
epithelial type III IF 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
astrocytemechanical strength[14] 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. The protein was named and first isolated and characterized by Lawrence F. Eng in 1969.[15] In humans, it is located on the long arm of
chromosome 17.[16]
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.[17] 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,[18] which can allow for specialization and increased variability.
To form networks, the initial GFAP dimers combine to make staggered
tetramers,[19] 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.[17] 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.[20]
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.[23] There are different sets of kinases at work;
cdc2kinase 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.[24] 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.[25] 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.[26] Biochemical studies of GFAP have shown
MgCl2 and/or
calcium/
calmodulin dependent
phosphorylation at various serine or
threonine residues by
PKC and
PKA[27] 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[28] and
brain.[29]
Meningoencephalitis is the predominant clinical presentation of autoimmune GFAP astrocytopathy in published case series.[30] It also can appear associated with
encephalomyelitis and parkinsonism.[31]
Disease states
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[32] and is partially caused by
up-regulation of GFAP.[33]
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.[34] The cellular mechanism of the disease is the presence of
cytoplasmic accumulations containing GFAP and
heat shock proteins, known as
Rosenthal fibers.[35] Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.[36] Some of these mutations have been proposed to be detrimental to
cytoskeleton formation as well as an increase in
caspase 3 activity,[37] which would lead to increased
apoptosis of cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.
The generally high abundance of GFAP in the
CNS has led to a great interest in GFAP as a blood
biomarker of acute injury to the brain and spinal cord in different types of disease mechanisms, such as
traumatic brain injury and
cerebrovascular disease.[43] Elevated blood levels of GFAP are also found in neuroinflammatory diseases, such as
multiple sclerosis and
neuromyelitis optica, a disease targeting astrocytes.[43] In a study of 22 child patients undergoing
extracorporeal 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.[44]
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
ADpathology.[47]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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): 152–154.
doi:
10.1006/geno.1998.5360.
PMID9693047.
^
abJacque CM, Vinner C, Kujas M, Raoul M, Racadot J, Baumann NA (January 1978). "Determination of glial fibrillary acidic protein (GFAP) in human brain tumors". Journal of the Neurological Sciences. 35 (1): 147–155.
doi:
10.1016/0022-510x(78)90107-7.
PMID624958.
S2CID10224197.
^Roessmann U, Velasco ME, Sindely SD, Gambetti P (October 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.
PMID6998542.
S2CID38131934.
^Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H (January 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. 90 (1): 53–61.
doi:
10.1016/s0248-4900(98)80232-3.
PMID9691426.
S2CID31851422.
^Maunoury R, Portier MM, Léonard N, McCormick D (December 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.
doi:
10.1016/0165-5728(91)90167-6.
PMID1720132.
S2CID3766335.
^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.
PMID11993850.
^von Koskull H (1984). "Rapid identification of glial cells in human amniotic fluid with indirect immunofluorescence". Acta Cytologica. 28 (4): 393–400.
PMID6205529.
^Kasantikul V, Shuangshoti S (May 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.
PMID2654484.
S2CID34069861.
^Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, et al. (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 Research. 51 (5): 1553–1560.
PMID1847665.
^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". Molecular Aspects of Development and Aging of the Nervous System. Advances in Experimental Medicine and Biology. Vol. 265. pp. 41–52.
doi:
10.1007/978-1-4757-5876-4_4.
ISBN978-1-4757-5878-8.
PMID2165732.
^Harrison BC, Mobley PL (January 1992). "Phosphorylation of glial fibrillary acidic protein and vimentin by cytoskeletal-associated intermediate filament protein kinase activity in astrocytes". Journal of Neurochemistry. 58 (1): 320–327.
doi:
10.1111/j.1471-4159.1992.tb09313.x.
PMID1727439.
S2CID28248825.
^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): 425–432.
PMID3548695.
^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.
PMID4038838.
S2CID1411700.
^Allen A, Gulhar S, Haidari R, Martinez JP, Bekenstein J, DeLorenzo R, et al. (January 2020). "Autoimmune glial fibrillary acidic protein astrocytopathy resulting in treatment-refractory flaccid paralysis". Multiple Sclerosis and Related Disorders. 39: 101924.
doi:
10.1016/j.msard.2019.101924.
PMID31927153.
S2CID210166834.
^Tomczak A, Su E, Tugizova M, Carlson AM, Kipp LB, Feng H, Han MH (December 2019). "A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism". Multiple Sclerosis and Related Disorders. 39: 101900.
doi:
10.1016/j.msard.2019.101900.
PMID31881522.
S2CID209498996.
^Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (January 2001). "Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease". Nature Genetics. 27 (1): 117–120.
doi:
10.1038/83679.
PMID11138011.
S2CID10159452.
^Cullen KM, Halliday GM (1994). "Chronic alcoholics have substantial glial pathology in the forebrain and diencephalon". Alcohol and Alcoholism. 2: 253–257.
PMID8974344.
^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". Experimental Cell Research. 278 (2): 175–183.
doi:
10.1006/excr.2002.5575.
PMID12169273.
Cáceres-Marzal C, Vaquerizo J, Galán E, Fernández S (October 2006). "Early mitochondrial dysfunction in an infant with Alexander disease". Pediatric Neurology. 35 (4): 293–296.
doi:
10.1016/j.pediatrneurol.2006.03.010.
PMID16996408.