Peripherin
Encyclopedia
Peripherin is a protein
that in humans is encoded by the PRPH gene
.
Peripherin is a type III Intermediate filament
(IF) 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 as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III IF proteins such as desmin
, vimentin
and glial fibrillary acidic protein
. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also coexist with neurofilaments in several neuronal types. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.
Peripherin, first named such in 1984, was also known as 57 kDa neuronal intermediate filament prior to 1990. In 1987, a second distinct peripherally located retinal rod protein was also given the name peripherin. To distinguish between the two, this second protein is referred to peripherin 2
or peripherin/RDS (retinal degeneration slow) for its location and role in retinal disease.
cell lines and in rat pheochromocytoma
cells. It is classified by gene structure and coding sequence as a type III IF protein because of its homology with vimentin, GFAP and desmin. All IF proteins share a common secondary structure consisting of three main domains, the most conserved of which is the central α-helical rod domain. This central coil is capped by non-helical head (N-terminal) and tail (C-terminal) domains. The α-helical rod domain contains repeating segments of hydrophobic amino acids, such that the first and fourth residues of every set of seven amino acids are usually nonpolar. This specific structure enables two IF polypeptides to coil together and create a "hydrophobic seal". The rod also contains specific placement of alternating acidic and basic residues, many of which are spaced 4 aa apart. This spacing is optimal for the formation of ionic salt bridges which serve to stabilize the α-helical rod through intrachain interactions. A switch from intrachain salt bridges to interchain ionic associations may assist in IF assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers. The head and tail regions of IF proteins vary in length and amino acid composition, with greater variations in length occurring in the tail regions.
Peripherin, unlike keratin IFs, can self-assemble and exist as homopolymers (see polymer
). They can also heteropolymerize, or co-assemble, with other type III proteins or the light neurofilament subunit (NF-L) to form intermediate filament networks.Type III proteins like peripherin can exist in different states within a cell. These states include nonfilamentous particles which combine to firm short IFs, or squiggles, which come together to form long IFs that make up cytoskeletal networks. Studies of network assembly in spreading fibroblasts and differentiating nerve cells show that particles move along microtubules in a kinesin
- and dynein
-dependent manner and as spreading continues, the particles polymerize into intermediate filaments.
In addition to the main species of peripherin, 57 kDa, two other forms have been identified in mice: Per 61 and Per 56. These two alternatives were both made by alternative splicing
. Per 61 is created by introducing a 32 amino acid insertion within coil 2b of the α-helical rod domain of peripherin. Per 56 is made by a receptor on exon 9 of the peripherin gene transcript which induces a frameshift and replacement of C-terminal 21 amino acids with a new 8 amino acid sequence. The functions of these two alternative forms of peripherin are unknown. Per 57 and 56 are normally co-expressed whereas Per 61 is not found in normal peripherin expression in adult motor neurons.
. These include small-sized root ganglion neurons, lower motor neurons, sensory and motor neurons of the cranial nerves
, and autonomic neurons in ganglia and the enteric nervous system. It is also expressed in the CNS in a small set of brain stem and spinal cord neurons that have projections toward peripheral structures. Some of these structures include the hypothalamic magnocellular nuclei, pontine cholinergic nuclei, some cerebellar nuclei, and scattered neurons in the cerebral cortex. They can also be found in the ventral horn neurons and in the cholinergic laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) nuclei.
A comparison of peripherin expression in the posterior and lateral hypothalamus
in mice showed a sixty-fold higher expression in the posterior hypothalamus. This higher expression is due to the presence of peripherin in the tuberomammillary neurons of the mouse hypothalamus.
(NGF) plays the major role in the regulation of peripherin. It is both a transcriptional inducer and post-translational regulator of peripherin expression in PC12 and neuroblastoma cells. The mechanism of NGF-induced activation occurs through 5' flanking elements and intragenic sequences involving the TATA box
and other upstream elements as well as depression at a negative element. The specifc signals regulating peripherin expression in vivo are unknown. The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion
at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripehrin to only the small sized cells, however crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells.
The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor
, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.
The exact function of peripherin is unknown. Expression of peripherin in development is greatest during the axonal growth phase and decreases postnatally, which suggests a role in neurite elongation and axonal guidance during development. Expression is also increased after axonal injury, such as peripheral axotomy in motor neurons and dorsal root ganglia. This upregulation implies that peripherin may also play a role in axon regeneration. However, experiments using peripherin depleted PC12 cells
and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes. In these experiments, peripehrin deficiency did produce an upregulation of α-internexin
, indicating the possibility that this type IV IF makes up for the loss of peripherin. Future studies of double knockout mice for both the peripehrin and α-internexin genes might address this theory. However, it is interesting to note that while most peripherin knockout mice displayed normal neuron growth, its absence did affect development of a subset of unmyelinated sensory axons. In such mice, there was a "34% reduction in the number of L5 unmyelinated sensory fibers that correlated with a decreased binding of the lectin
IB4."
(cDNA) thus far described are those for rat, mouse and Xenopus peripherin. The use of a mouse cDNA probe during the in situ hybridization
procedure allowed for the localization of the PRPH gene to the E-F region of mouse chromosome 15 and the q12-q13 region of human chromosome 12.
The overall structure of the peripherin gene is nine exons separated by eight introns. This configuration is conserved among the three known mammalian species with known coding for peripherin, namely human, rat and mouse. The nucleotide sequences of human and rat exons were 90% identical and produced a predicted protein that differed at only 18 of 475 amino acid residues. Comparison of introns 1 and 2 also yielded high homology of conserved segments. The 5' flanking regions and regulatory sequences were also very similar and a nerve growth factor negative regulatory element, a Hox protein (See Hox gene) binding site, and a heat shock element were found in all known peripherin genes.
are characteristic of patients with ALS, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with ALS. Peripherin has been found in such spheroids in conjunction with other neurofilaments in other neuronal diseases, thus suggesting that peripherin may play a role in ALS pathogenesis.
mouse peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in ALS tissues. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.
variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift
mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the neurofilament
network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human ALS cases.
The second variant consisted of an amino acid substitution from aspartate to tyrosine
as a result of a single point mutation
in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in ALS pathogenesis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms.
. It may be possible to regulate this aggregation and apoptosis using siRNAs
and PKCε. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.
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 in humans is encoded by the PRPH gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Peripherin is a type III 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...
(IF) protein expressed mainly in neurons of the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
. It is also found in neurons of 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...
that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III IF proteins such as 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...
, 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...
and glial fibrillary acidic protein
Glial fibrillary acidic protein
Glial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also coexist with neurofilaments in several neuronal types. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.
Peripherin, first named such in 1984, was also known as 57 kDa neuronal intermediate filament prior to 1990. In 1987, a second distinct peripherally located retinal rod protein was also given the name peripherin. To distinguish between the two, this second protein is referred to peripherin 2
Peripherin 2
Peripherin-2 is a protein, that in humans is encoded by the PRPH2 gene. Peripherin-2 is found in the rod and cone cells of the retina of the eye...
or peripherin/RDS (retinal degeneration slow) for its location and role in retinal disease.
Structure and properties
Peripherin was discovered as being the major intermediate filament in neuroblastomaNeuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
cell lines and in rat pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
cells. It is classified by gene structure and coding sequence as a type III IF protein because of its homology with vimentin, GFAP and desmin. All IF proteins share a common secondary structure consisting of three main domains, the most conserved of which is the central α-helical rod domain. This central coil is capped by non-helical head (N-terminal) and tail (C-terminal) domains. The α-helical rod domain contains repeating segments of hydrophobic amino acids, such that the first and fourth residues of every set of seven amino acids are usually nonpolar. This specific structure enables two IF polypeptides to coil together and create a "hydrophobic seal". The rod also contains specific placement of alternating acidic and basic residues, many of which are spaced 4 aa apart. This spacing is optimal for the formation of ionic salt bridges which serve to stabilize the α-helical rod through intrachain interactions. A switch from intrachain salt bridges to interchain ionic associations may assist in IF assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers. The head and tail regions of IF proteins vary in length and amino acid composition, with greater variations in length occurring in the tail regions.
Peripherin, unlike keratin IFs, can self-assemble and exist as homopolymers (see polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
). They can also heteropolymerize, or co-assemble, with other type III proteins or the light neurofilament subunit (NF-L) to form intermediate filament networks.Type III proteins like peripherin can exist in different states within a cell. These states include nonfilamentous particles which combine to firm short IFs, or squiggles, which come together to form long IFs that make up cytoskeletal networks. Studies of network assembly in spreading fibroblasts and differentiating nerve cells show that particles move along microtubules in a kinesin
Kinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells. Kinesins move along microtubule filaments, and are powered by the hydrolysis of ATP . The active movement of kinesins supports several cellular functions including mitosis, meiosis and transport of cellular...
- and dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
-dependent manner and as spreading continues, the particles polymerize into intermediate filaments.
In addition to the main species of peripherin, 57 kDa, two other forms have been identified in mice: Per 61 and Per 56. These two alternatives were both made by alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
. Per 61 is created by introducing a 32 amino acid insertion within coil 2b of the α-helical rod domain of peripherin. Per 56 is made by a receptor on exon 9 of the peripherin gene transcript which induces a frameshift and replacement of C-terminal 21 amino acids with a new 8 amino acid sequence. The functions of these two alternative forms of peripherin are unknown. Per 57 and 56 are normally co-expressed whereas Per 61 is not found in normal peripherin expression in adult motor neurons.
Tissue distribution
Peripherin is widely expressed in the cell body and axons of neurons in the peripheral nervous systemPeripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
. These include small-sized root ganglion neurons, lower motor neurons, sensory and motor neurons of the cranial nerves
Cranial nerves
Cranial nerves are nerves that emerge directly from the brain, in contrast to spinal nerves, which emerge from segments of the spinal cord. In humans, there are traditionally twelve pairs of cranial nerves...
, and autonomic neurons in ganglia and the enteric nervous system. It is also expressed in the CNS in a small set of brain stem and spinal cord neurons that have projections toward peripheral structures. Some of these structures include the hypothalamic magnocellular nuclei, pontine cholinergic nuclei, some cerebellar nuclei, and scattered neurons in the cerebral cortex. They can also be found in the ventral horn neurons and in the cholinergic laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) nuclei.
A comparison of peripherin expression in the posterior and lateral hypothalamus
Lateral hypothalamus
The lateral hypothalamus or lateral hypothalamic area is a part of the hypothalamus.It is concerned with hunger. Damage to this area can cause reduced food intake...
in mice showed a sixty-fold higher expression in the posterior hypothalamus. This higher expression is due to the presence of peripherin in the tuberomammillary neurons of the mouse hypothalamus.
Regulatory mechanisms
Nerve growth factorNerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
(NGF) plays the major role in the regulation of peripherin. It is both a transcriptional inducer and post-translational regulator of peripherin expression in PC12 and neuroblastoma cells. The mechanism of NGF-induced activation occurs through 5' flanking elements and intragenic sequences involving the TATA box
TATA box
The TATA box is a DNA sequence found in the promoter region of genes in archaea and eukaryotes; approximately 24% of human genes contain a TATA box within the core promoter....
and other upstream elements as well as depression at a negative element. The specifc signals regulating peripherin expression in vivo are unknown. The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripehrin to only the small sized cells, however crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells.
The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.
Function
The diverse properties of intermediate filaments, compared with the conserved microtubule and actin filament proteins, could be responsible for the distinguishing molecular shapes of different cell types. In nerve cells, for example, the expressions of different types of IFs relates to the change in shape during development. Early stages of development in neurons is marked by the outgrowth of neurites and axons contributing to the cells asymmetric shape. During these transitions in cell shape, only homopolymer type III intermediate filaments, such as those with peripherin, are made. As the nerve cell matures, these type III IFs are replaced by more complex type IV neurofilaments expanding the diameter of axons in order to attain normal velocities of action potentials.The exact function of peripherin is unknown. Expression of peripherin in development is greatest during the axonal growth phase and decreases postnatally, which suggests a role in neurite elongation and axonal guidance during development. Expression is also increased after axonal injury, such as peripheral axotomy in motor neurons and dorsal root ganglia. This upregulation implies that peripherin may also play a role in axon regeneration. However, experiments using peripherin depleted PC12 cells
PC12 cells
PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla. PC12 cells stop dividing and terminally differentiate when treated with nerve growth factor...
and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes. In these experiments, peripehrin deficiency did produce an upregulation of α-internexin
Internexin
Internexin, alpha-internexin, is a Class IV intermediate filament approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord. The protein copurifies with other neurofilament subunits, as it was originally discovered, however in some mature neurons it can be the...
, indicating the possibility that this type IV IF makes up for the loss of peripherin. Future studies of double knockout mice for both the peripehrin and α-internexin genes might address this theory. However, it is interesting to note that while most peripherin knockout mice displayed normal neuron growth, its absence did affect development of a subset of unmyelinated sensory axons. In such mice, there was a "34% reduction in the number of L5 unmyelinated sensory fibers that correlated with a decreased binding of the lectin
Lectin
Lectins are sugar-binding proteins that are highly specific for their sugar moieties. They play a role in biological recognition phenomena involving cells and proteins. For example, some viruses use lectins to attach themselves to the cells of the host organism during infection...
IB4."
Gene (PRPH)
The complete sequence of the human (GenBank L14565), rat (GenBank M26232) and mouse (EMBL X59840) peripherin genes (PRPH) have been reported and complementary DNAsComplementary DNA
In genetics, complementary DNA is DNA synthesized from a messenger RNA template in a reaction catalyzed by the enzyme reverse transcriptase and the enzyme DNA polymerase. cDNA is often used to clone eukaryotic genes in prokaryotes...
(cDNA) thus far described are those for rat, mouse and Xenopus peripherin. The use of a mouse cDNA probe during the in situ hybridization
In situ hybridization
In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue...
procedure allowed for the localization of the PRPH gene to the E-F region of mouse chromosome 15 and the q12-q13 region of human chromosome 12.
The overall structure of the peripherin gene is nine exons separated by eight introns. This configuration is conserved among the three known mammalian species with known coding for peripherin, namely human, rat and mouse. The nucleotide sequences of human and rat exons were 90% identical and produced a predicted protein that differed at only 18 of 475 amino acid residues. Comparison of introns 1 and 2 also yielded high homology of conserved segments. The 5' flanking regions and regulatory sequences were also very similar and a nerve growth factor negative regulatory element, a Hox protein (See Hox gene) binding site, and a heat shock element were found in all known peripherin genes.
Clinical significance
Protein and neurofilamentous aggregatesProtein aggregation
Protein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....
are characteristic of patients with ALS, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with ALS. Peripherin has been found in such spheroids in conjunction with other neurofilaments in other neuronal diseases, thus suggesting that peripherin may play a role in ALS pathogenesis.
Alternative splicing
An alternatively splicedAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
mouse peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in ALS tissues. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.
Mutations
Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in ALS pathogenesis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphicPolymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the 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...
network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human ALS cases.
The second variant consisted of an amino acid substitution from aspartate to tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
as a result of a single point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in ALS pathogenesis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms.
Potential applications
Possible involvement of intermediate filaments such as peripherin in neurodegenerative diseases is currently being investigated. Interactions between intermediate filaments and other proteins are also being pursued. Peripherin has been shown to associate with protein kinase Cε (PKCε), inducing its aggregation and leading to increased apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. It may be possible to regulate this aggregation and apoptosis using siRNAs
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
and PKCε. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.