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Peripherin, a 58-kDa, type III intermediate filament (IF) protein expressed in the peripheral nervous system (PNS) and in defined subsets of neurons in the central nervous system (CNS), is thought to play an integral role in the development of the highly plastic neuronal cytoskeleton and to provide mechanical support to terminally differentiated neurons. Peripherin expression is a dynamically regulated process that involves mediation by a number of cis- and trans-acting factors throughout the gene region. Peripherin expression is characterized by a stoichiometric ratio of functionally distinct isoforms that arise as a result of alternative splicing and translation. Pathologically, peripherin has been implicated in several human diseases but is best known for its descriptions in the literature of the devastating motor neuron disease, amyotrophic lateral sclerosis (ALS). Here, peripherin is a component of the major pathologic hallmarks of both familial and sporadic ALS – intracellular aggregates – and is found upregulated and abnormally spliced in areas of disease. Moreover, peripherin mutations have been associated with sporadic ALS cases, and transgenic overexpression of peripherin in mice recapitulates some of the clinical and pathologic aspects of ALS. Peripherin pathology represents a point-of-convergence for both the familial and sporadic forms of ALS; however, despite our increasing knowledge about peripherin biology, little is known about the nature of its involvement in disease pathogenesis. This chapter is aimed at providing the first intensive review of peripherin biology and its involvement in disease. [ABSTRACT FROM AUTHOR]

The basic structure of neural intermediate filament (IF) molecules is known, as are the modes of interaction that direct these molecules into highly specific and fully functional IF. It has been established that the IF molecule is a dimer and that its two constituent chains lie parallel to each other and in axial register. The molecule has a tripartite structure with a central, α-helical, coiled-coil–rich region (the rod domain) separating the head (the region N-terminal to the rod) from the tail (the region C-terminal to the rod). A regularity in the linear dispositions of the charged residues in the longest coiled-coil segments aids assembly through the formation of numerous intermolecular ionic interactions. By analogy with the well-defined surface lattice structure of trichocyte keratin (deduced from the extensive x-ray diffraction data available), the surface lattice structure of neural IF can also be deduced, primarily from the pattern of cross-links induced between molecules. Using scanning transmission electron microscopy (STEM) and cryo-tomographic data, the neural IF are likely to have a four-protofibril structure containing 32 chains in section. Assembly occurs through a rapid lateral aggregation of about eight tetramers to form a unit-length-filament (ULF), with each of these tetramers consisting of a half-staggered, antiparallel pair of molecules. Elongation occurs through the axial aggregation of ULF to form immature IF about 16 nm in diameter and many micrometers in length. Radial compaction then takes place resulting in close packing of the molecular filaments and the formation of IF with diameter in the range 8–12 nm. [ABSTRACT FROM AUTHOR]