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.
History
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.
Gene
The complete sequence of the human (GenBank L14565), rat (GenBank M26232) and mouse (EMBL X59840) peripherin genes (PRPH) have been reported and complementary DNAs (cDNA) thus far described are those for rat, mouse and Xenopus peripherin.
Alternative splicing
An alternatively spliced 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 tissues affected by amyotrophic lateral sclerosis. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.
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. 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. 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.
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.
Mutations
Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in the pathogenesis of amyotrophic lateral sclerosis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphic 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 cases of amyotrophic lateral sclerosis.
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 amyotrophic lateral sclerosis 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.
Amyotrophic lateral sclerosis
Protein and neurofilamentous aggregates are characteristic of patients with amyotrophic lateral sclerosis, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with amyotrophic lateral sclerosis. 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 the pathogenesis of amyotrophic lateral sclerosis. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.