GFAP is closely related to the other three non-epithelial type III IF family members,vimentin,desmin andperipherin, which are all involved in the structure and function of the cell'scytoskeleton. GFAP is thought to help to maintainastrocytemechanical strength[14] as well as the shape of cells, but its exact function remains poorly understood, despite the number of studies using it as acell 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 ofchromosome 17.[16]
Type III intermediate filaments contain three domains, named the head, rod and tail domains. The specificDNA sequence for the rod domain may differ between different type III intermediate filaments, but the structure of theprotein is highly conserved. This rod domain coils around that of another filament to form adimer, with theN-terminal andC-terminal of each filament aligned. Type III filaments such as GFAP are capable of forming bothhomodimers andheterodimers; GFAP canpolymerize with other type III proteins.[17] GFAP and other type III IF proteins cannot assemble withkeratins, the type I and IIintermediate 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 staggeredtetramers,[19] which are the basic subunits of anintermediate filament. Since rod domains alonein 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 conservedarginines and anaromatic residue that have been shown to be required for proper assembly.[20]
GFAP has been shown to play a role inmitosis 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 theG2 phase transition, while other GFAPkinases are active at thecleavage furrow alone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. Studies have also shown that GFAPknockout mice undergo multiple degenerative processes including abnormalmyelination,white matter structure deterioration, and functional/structural impairment of theblood–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 ascell-cell communication.In vitro, usingantisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons.[25] Studies have also shown thatPurkinje cells in GFAP knockout mice do not exhibit normal structure, and these mice demonstrate deficits inconditioning experiments such as the eye-blink task.[26] Biochemical studies of GFAP have shownMgCl2 and/orcalcium/calmodulin dependentphosphorylation at variousserine orthreonine residues byPKC andPKA[27] which are twokinases that are important for thecytoplasmic 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 ofglial scars in a multitude of locations throughout the CNS including theeye[28] andbrain.[29]
There are multiple disorders associated with improper GFAP regulation, and injury can causeglial cells to react in detrimental ways.Glial scarring is a consequence of severalneurodegenerative conditions, as well as injury that severs neural material. The scar is formed byastrocytes interacting withfibrous tissue to re-establish the glial margins around the central injury core[30] and is partially caused byup-regulation of GFAP.[31]
Another condition directly related to GFAP isAlexander 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), andseizures.[32] The cellular mechanism of the disease is the presence ofcytoplasmic accumulations containing GFAP andheat shock proteins, known asRosenthal fibers.[33] Mutations in thecoding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers.[34] Some of these mutations have been proposed to be detrimental tocytoskeleton formation as well as an increase incaspase 3 activity,[35] which would lead to increasedapoptosis of cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.
The generally high abundance of GFAP in theCNS has led to a great interest in GFAP as a bloodbiomarker of acute injury to the brain and spinal cord in different types of disease mechanisms, such astraumatic brain injury andcerebrovascular disease.[41] After an ischemic stroke, blood levels of GFAP peak after three days and correlates strongly with infarct volume.[42] Elevated blood levels of GFAP are also found in neuroinflammatory diseases, such asmultiple sclerosis andneuromyelitis optica, a disease targeting astrocytes.[41] In a study of 22 child patients undergoingextracorporeal 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.[43]
Although GFAP alpha is the only isoform which is able to assemble homomerically, GFAP has 8 differentisoforms which label distinct subpopulations ofastrocytes 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 withneural 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 ofmorphologies including processes of up to 0.95 mm (seen in the human brain). The expression of GFAP+1 positive astrocytes is linked with old age and the onset ofADpathology.[46]
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