Role of the Intermediate Filament Protein Peripherin in Health and Disease

Abstract

Intermediate filaments are the most heterogeneous class among cytoskeletal elements. While some of them have been well-characterized, little is known about peripherin. Peripherin is a class III intermediate filament protein with a specific expression in the peripheral nervous system. Epigenetic modifications are involved in this cell-type-specific expression. Peripherin has important roles in neurite outgrowth and stability, axonal transport, and axonal myelination. Moreover, peripherin interacts with proteins involved in vesicular trafficking, signal transduction, DNA/RNA processing, protein folding, and mitochondrial metabolism, suggesting a role in all these processes. This review collects information regarding peripherin gene regulation, post-translational modifications, and functions and its involvement in the onset of a number of diseases.

Keywords: Charcot–Marie–Tooth disease; amyotrophic lateral sclerosis; diabetes; intermediate filaments; neurodegeneration; neurodegenerative diseases; neurons; peripheral nervous system; peripherin.

Figure 1

Peripherin gene and protein structure. The peripherin gene is composed of nine exons separated by eight introns. Several isoforms of the peripherin protein exist. Peripherin isoforms are generated by premature stop codon (Per–28), intron retention, premature stop codon (Per–32), in-frame downstream initiation codon (Per–45), alternative splicing (Per–56), and insertion (Per–61). Per–61 is expressed only in mice, Per–32 only in humans. The predominant form of peripherin is Per–58. Peripherin shows several post-translational modifications such as phosphorylation at Ser66 and Tyr474 and nitration at Tyr17 and Tyr376. The known important functions of peripherin in neurons are listed.

Figure 2

Peripherin is associated with a number of diseases. In Charcot–Marie–Tooth type 2B, disease-causing RAB7A mutations alter peripherin assembly. In amyotrophic lateral sclerosis, the expression of Per-28 is related to the appearance of cytoplasmic aggregates. In diabetic patients, peripherin autoantibodies have been detected is serum. Finally, peripherin promotes the entrance and assembly of EV-A71 enterovirus.