Wikipedia

Glial fibrillary acidic protein

Glial fibrillary acidic protein(GFAP) is aproteinthat is encoded by theGFAPgenein humans.[5]It is atype III intermediate filament(IF) protein that is expressed by numerous cell types of thecentral nervous system(CNS), includingastrocytes[6]andependymal cellsduring development.[7]GFAP has also been found to be expressed inglomeruliandperitubularfibroblaststaken from rat kidneys,[8]Leydig cellsof the testis in both hamsters[9]and humans,[10]humankeratinocytes,[11]humanosteocytesandchondrocytes[12]and stellate cells of thepancreasandliverin rats.[13]

GFAP
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesGFAP,ALXDRD, glial fibrillary acidic protein
External IDsOMIM:137780;MGI:95697;HomoloGene:1554;GeneCards:GFAP;OMA:GFAP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2670

14580

Ensembl

ENSG00000131095

ENSMUSG00000020932

UniProt

P14136

P03995

RefSeq (mRNA)

NM_002055
NM_001131019
NM_001242376
NM_001363846

NM_001131020
NM_010277

RefSeq (protein)

NP_001124491
NP_001229305
NP_002046
NP_001350775

NP_001124492
NP_034407

Location (UCSC)Chr 17: 44.9 – 44.92 MbChr 11: 102.78 – 102.79 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

GFAP is closely related to the other three non-epithelialtype III IF family members,vimentin,desminandperipherin,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]

Structure

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Type III intermediate filaments contain three domains, named the head, rod and tail domains. The specificDNAsequence for the rod domain may differ between different type III intermediate filaments, but the structure of theproteinis highly conserved. This rod domain coils around that of another filament to form adimer,with theN-terminalandC-terminalof each filament aligned. Type III filaments such as GFAP are capable of forming bothhomodimersandheterodimers;GFAP canpolymerizewith 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 vitrodo 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 conservedargininesand anaromaticresidue that have been shown to be required for proper assembly.[20]

Function in the central nervous system

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GFAP is expressed in thecentral nervous systemin astrocyte cells, and the concentration of GFAP differs between different regions in theCNS,where the highest levels are found inmedulla oblongata,cervical spinal cordandhippocampus.[6][21][22]It is involved in many important CNS processes, including cell communication and the functioning of theblood brain barrier.

GFAP has been shown to play a role inmitosisby 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;cdc2kinaseacts only at theG2 phasetransition, while other GFAPkinasesare active at thecleavage furrowalone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. Studies have also shown that GFAPknockout miceundergo multiple degenerative processes including abnormalmyelination,white matterstructure deterioration, and functional/structural impairment of theblood–brain barrier.[24]These data suggest that GFAP is necessary for many critical roles in theCNS.

GFAP is proposed to play a role inastrocyte-neuroninteractions 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 cellsin GFAP knockout mice do not exhibit normal structure, and these mice demonstrate deficits inconditioning experimentssuch as the eye-blink task.[26]Biochemical studies of GFAP have shownMgCl2and/orcalcium/calmodulindependentphosphorylationat variousserineorthreonineresidues byPKCandPKA[27]which are twokinasesthat are important for thecytoplasmictransduction 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 scarsin a multitude of locations throughout the CNS including theeye[28]andbrain.[29]

Autoimmune GFAP astrocytopathy

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In 2016 a CNS inflammatory disorder associated with anti-GFAPantibodieswas described. Patients withautoimmune GFAP astrocytopathydeveloped meningoencephalomyelitis with inflammation of themeninges,the brainparenchyma,and thespinal cord.About one third of cases were associated with variouscancersand many also expressed other CNSautoantibodies.

Meningoencephalitisis the predominant clinical presentation of autoimmune GFAP astrocytopathy in published case series.[30]It also can appear associated withencephalomyelitisand parkinsonism.[31]

Disease states

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GFAPimmunostainingin a glial neoplasm (anaplastic astrocytoma)
GFAPimmunostainingof an astrocyte in cell culture in red and counterstained forvimentinin green. GFAP and vimentin colocalize in cytoplasmicintermediate filaments,so the astrocyte appears yellow. Nuclear DNA is stained blue withDAPI.Antibodies, cell preparation and image generated byEnCor Biotechnology Inc.

There are multiple disorders associated with improper GFAP regulation, and injury can causeglial cellsto react in detrimental ways.Glial scarringis a consequence of severalneurodegenerativeconditions, as well as injury that severs neural material. The scar is formed byastrocytesinteracting withfibrous tissueto re-establish the glial margins around the central injury core[32]and is partially caused byup-regulationof GFAP.[33]

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.[34]The cellular mechanism of the disease is the presence ofcytoplasmicaccumulations containing GFAP andheat shock proteins,known asRosenthal fibers.[35]Mutations in thecoding regionof GFAP have been shown to contribute to the accumulation of Rosenthal fibers.[36]Some of these mutations have been proposed to be detrimental tocytoskeletonformation as well as an increase incaspase 3activity,[37]which would lead to increasedapoptosisof cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.

Notably, the expression of some GFAPisoformshave been reported to decrease in response toacuteinfection orneurodegeneration.[38] Additionally, reduction in GFAP expression has also been reported inWernicke's encephalopathy.[39]TheHIV-1viral envelopeglycoproteingp120can directly inhibit thephosphorylationof GFAP and GFAP levels can be decreased in response tochronicinfection with HIV-1,[40]varicella zoster,[41]andpseudorabies.[42]Decreases in GFAP expression have been reported inDown's syndrome,schizophrenia,bipolar disorderanddepression.[38]

The generally high abundance of GFAP in theCNShas led to a great interest in GFAP as a bloodbiomarkerof acute injury to the brain and spinal cord in different types of disease mechanisms, such astraumatic brain injuryandcerebrovascular disease.[43]Elevated blood levels of GFAP are also found in neuroinflammatory diseases, such asmultiple sclerosisandneuromyelitis optica,a disease targeting astrocytes.[43]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.[44]

Interactions

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Glial fibrillary acidic protein has been shown tointeractwithMEN1[45]andPSEN1.[46]

Isoforms

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Although GFAP Alpha is the only isoform which is able to assemble homomerically, GFAP has 8 differentisoformswhich label distinct subpopulations ofastrocytesin 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 ofmorphologiesincluding 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.[47]

See also

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References

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Further reading

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