Glial fibrillary acidic protein
Encyclopedia
Glial fibrillary acidic protein (GFAP) is an intermediate filament
(IF) protein
that was thought to be specific for astrocytes in the central nervous system
(CNS). Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells. GFAP has also been located in rat kidney glomeruli and peritubular fibroblasts, leydig cells of testis, skin keratinocytes, osteocytes of bones, chondrocytes of epiglottis, bronchus, and stellate-shaped cells of the pancreas and liver. First described in 1971, GFAP is a type III IF protein that maps, in humans, to 17q21. 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, 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.
, 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). 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, which can allow for specialization and increased variability.
To form networks, the initial dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament
. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation. The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two arginine
s and an aromatic residue that have been shown to be required for proper assembly. The sizes of the head and tail regions are quite different between GFAP and its more common counterpart vimentin
, which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network.
and hormone
levels. Increased expression of this protein is evident in a number of circumstances, and is commonly referred to as "Astrocytic
activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma
(tumor) cell lines, but not in mature astroctyes. This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually.
In mature cells, the most studied avenue of change in filament amount is the phosphorylation
of GFAP, which can occur at five different sites on the protein. This post-translational modification occurs at the head domain and alters the charge of the protein, resulting in disaggregation and subsequent break down of the filaments. The relationship between the level of filamentous GFAP present is usually in a stable equilibrium with free protein, and currently the functional importance of the alteration in the levels of GFAP is not fully understood.
in astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, 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. 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.
In mature cells, using knockout mice, multiple functions have been associated with GFAP expression. These knockout mice lack intermediate filaments in the hippocampus
and in the white matter
of the spinal cord. Studies have also shown that GFAP knockout mice undergo multiple degenerative processes including abnormal myelination, white matter structure deterioration, and alterations in the blood-brain barrier
. These data suggest that GFAP is involved in maintenance of CNS myelin integrity.
GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons. 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. Therefore, GFAP is thought to play an important role in the maintenance of Purkinje cell communication, and possibly many other neural cell types.
.
Another condition directly related to GFAP is Alexander disease
. This disease is a rare genetic disorder and predominantly affects males. Its symptoms include: mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures. The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers.
The relationship between GFAP and Alexander disease is not completely understood, but mutations in the coding region of the GFAP gene are associated with the presence of this condition. These mutations are proposed to act in a gain of function manner, as the knockout GFAP phenotype does not resemble the cytoplasmic GFAP mass. The relationship between the Rosenthal fibers and the observable phenotypes is believed to be due to interference in astrocyte interactions with other cells, and a possible inability to maintain the blood brain barrier.
Notably, some isoforms of GFAP have been reported to decrease in response to acute
infection or neurodegeneration
.
Additionally, reduction in GFAP expression has also been reported in wernicke's encephalopathy.
GFAP can be phosphorylated at five sites (Thr7, Ser8, Ser13, Ser17 and Ser38) in response to numerous stimuli. The expression of some GFAP isoforms are decreased in response to tumour necrosis factor-alpha, basic fibroblast growth factor
, and glucocorticoids in cell cultures. 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, varicella zoster, and pseudorabies
. GFAP decreases have been reported in Down's syndrome, schizophrenia
, bipolar disorder
and depression
.
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. GFAP levels are already used as a marker of neurologic damage in adults who suffer stroke
s and traumatic brain injuries.
with MEN1
and PSEN1
.
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
(IF) protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that was thought to be specific for astrocytes in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells. GFAP has also been located in rat kidney glomeruli and peritubular fibroblasts, leydig cells of testis, skin keratinocytes, osteocytes of bones, chondrocytes of epiglottis, bronchus, and stellate-shaped cells of the pancreas and liver. First described in 1971, GFAP is a type III IF protein that maps, in humans, to 17q21. It is closely related to its non-epithelial family members, vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, desmin
Desmin
Desmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
, and peripherin
Peripherin
Peripherin is a protein that in humans is encoded by the PRPH gene.Peripherin is a type III Intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such...
, which are all involved in the structure and function of the cell’s cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
. GFAP is thought to help to maintain astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
mechanical strength, 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.
Structure
Type III intermediate filaments contain three domains, the most conserved of which is the rod domain. The specific DNA sequence for this region of the protein may differ between the different intermediate filament genes for type III proteins, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, 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
Neurofilament
Neurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
protein (NF-L). Interestingly, GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
s. In cells that express both proteins, two separate intermediate filament networks form, which can allow for specialization and increased variability.
To form networks, the initial dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
. Since rods alone in vitro do not form filaments, the non-helical domains are necessary for filament formation. The remaining two regions, head and tail, have greater variability of sequence and structure. However, the head of GFAP contains two arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
s and an aromatic residue that have been shown to be required for proper assembly. The sizes of the head and tail regions are quite different between GFAP and its more common counterpart vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, which suggests that, when coassembled, they would align head-to-head rather than head-to-tail. This would allow for more plastic functionality of the intermediate filament network.
Protein expression
The amount of GFAP the cell produces is regulated by numerous processes, such as changes in cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
and hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
levels. Increased expression of this protein is evident in a number of circumstances, and is commonly referred to as "Astrocytic
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
activation". During development, vimentin, another type III intermediate filament, is colocalized with GFAP in immature glial cells, as well as glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
(tumor) cell lines, but not in mature astroctyes. This could indicate, due to the proposed head-to-head structure, that GFAP and vimentin filaments serve a very different purpose than each serves individually.
In mature cells, the most studied avenue of change in filament amount is the phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of GFAP, which can occur at five different sites on the protein. This post-translational modification occurs at the head domain and alters the charge of the protein, resulting in disaggregation and subsequent break down of the filaments. The relationship between the level of filamentous GFAP present is usually in a stable equilibrium with free protein, and currently the functional importance of the alteration in the levels of GFAP is not fully understood.
Cellular function
GFAP is expressed in the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
in astrocyte cells. It is involved in many cellular functioning processes, such as cell structure and movement, cell communication, and the functioning of the blood brain barrier.
GFAP has been shown to play a role in mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
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. There are different sets of kinases at work; cdc2 kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
acts only at the G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...
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.
In mature cells, using knockout mice, multiple functions have been associated with GFAP expression. These knockout mice lack intermediate filaments in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and in the white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
of the spinal cord. Studies have also shown that GFAP knockout mice undergo multiple degenerative processes including abnormal myelination, white matter structure deterioration, and alterations in the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. These data suggest that GFAP is involved in maintenance of CNS myelin integrity.
GFAP is also proposed to play a role in astrocyte-neuron interactions. In vitro, using antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons. 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. Therefore, GFAP is thought to play an important role in the maintenance of Purkinje cell communication, and possibly many other neural cell types.
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, and is partially caused by up-regulation of GFAP. The scar acts as a physical and chemical barrier to neuronal growth, and prevents neural regenerationRegeneration (biology)
In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organs, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. At its most...
.
Another condition directly related to GFAP is Alexander disease
Alexander disease
Alexander disease is a slowly progressing and fatal neurodegenerative disease. It is a very rare disorder which results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics....
. This disease is a rare genetic disorder and predominantly affects males. Its symptoms include: mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures. The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers.
The relationship between GFAP and Alexander disease is not completely understood, but mutations in the coding region of the GFAP gene are associated with the presence of this condition. These mutations are proposed to act in a gain of function manner, as the knockout GFAP phenotype does not resemble the cytoplasmic GFAP mass. The relationship between the Rosenthal fibers and the observable phenotypes is believed to be due to interference in astrocyte interactions with other cells, and a possible inability to maintain the blood brain barrier.
Notably, some isoforms of GFAP have been reported to decrease in response to acute
Acute (medicine)
In medicine, an acute disease is a disease with either or both of:# a rapid onset, as in acute infection# a short course ....
infection or neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
.
Additionally, reduction in GFAP expression has also been reported in wernicke's encephalopathy.
GFAP can be phosphorylated at five sites (Thr7, Ser8, Ser13, Ser17 and Ser38) in response to numerous stimuli. The expression of some GFAP isoforms are decreased in response to tumour necrosis factor-alpha, basic fibroblast growth factor
Basic fibroblast growth factor
Basic fibroblast growth factor, also known as bFGF, FGF2 or FGF-β, is a member of the fibroblast growth factor family.- Function :...
, and glucocorticoids in cell cultures. The HIV-1 viral envelope glycoprotein gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
can directly inhibit the phosphorylation of GFAP and GFAP levels can be decreased in response to chronic infection with HIV-1, varicella zoster, and pseudorabies
Pseudorabies
Pseudorabies is a viral disease in swine that is endemic in most parts of the world. It is caused by Suid herpesvirus 1 , which is also called Pseudorabies virus and is also known as Aujeszky's disease, and in cattle as mad itch. PRV is considered to be the most economically important viral...
. GFAP decreases have been reported in Down's syndrome, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
.
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. GFAP levels are already used as a marker of neurologic damage in adults who suffer stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s and traumatic brain injuries.
Interactions
Glial fibrillary acidic protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with MEN1
MEN1
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
and PSEN1
PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
.