Peripherin

563019132ENSG00000135406ENSMUSG00000023484P41219P15331NM_006262NM_001163588NM_001163589NM_013639NP_006253n/aPeripherin 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 as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks (networks formed from peripherin protein dimers), but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. 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 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 as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks (networks formed from peripherin protein dimers), but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. 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. Peripherin was discovered as being the major intermediate filament in neuroblastoma cell lines and in rat pheochromocytoma cells. It is classified by gene structure and coding sequence as a type III intermediate filament protein because of its homology with vimentin, glial fibrillary acidic protein, and desmin. All intermediate filament 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 intermediate filament 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 amino acids 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 intermediate filament assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers. The head and tail regions of intermediate filament 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. These squiggles 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 are 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 a 21 amino acid sequence in the C-terminal found on the dominant 57 form 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. Peripherin is widely expressed in the cell body and axons of neurons in the peripheral nervous system. 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 central nervous system in a small set of brainstem 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 posterior hypothalamus. 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 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, peripherin deficiency did produce an upregulation of α-internexin, indicating the possibility that this type IV intermediate filament makes up for the loss of peripherin. Future studies of double knockout mice for both the peripherin and α-internexin genes might address this theory. However, 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.'