Периферин: структура, функции и роль в нейродегенеративных заболеваниях.

Protein coding gene in the species Homo sapiens

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. 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.

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. 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 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.

Nerve growth factor (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 specific 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 peripherin 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 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.

Peripherin may be involved in the pathology of insulin dependent diabetes mellitus (or diabetes mellitus type 1) in animals; however, no direct linkage has been found in human patients. In a nonobese diabetic mouse model, peripherin has been found as a known autoantigen (See antigen). B cell clones reactive to peripherin have also been found in early stages of the disease. Since peripherin is expressed in both the peripheral nervous system and, in young animals, by islet beta cells, it is possible that the destruction of both peripheral nervous system elements and islet β cells in insulin dependent diabetes mellitus is due to the immune response to autoreactive peripherin.

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, inducing its aggregation and leading to increased apoptosis. It may be possible to regulate this aggregation and apoptosis using siRNAs and protein kinase Cε. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.