Posttranslational modification of proteins is a ubiquitous cellular mechanism for regulating protein function. Some of the most heavily modified neuronal proteins are cytoskeletal proteins of long myelinated axons referred to as neurofilaments (NFs). NFs are type IV intermediate filaments (IFs) that can be composed of four subunits, neurofilament heavy (NF-H), neurofilament medium (NF-M), neurofilament light (NF-L), and α-internexin. Within wild type axons, NFs are responsible for mediating radial growth, a process that determines axonal diameter. NFs are phosphorylated on highly conserved lysine-serine-proline (KSP) repeats located along the C-termini of both NF-M and NF-H within myelinated axonal regions. Phosphorylation is thought to regulate aspects of NF transport and function. However, a key pathological hallmark of several neurodegenerative diseases is ectopic accumulation and phosphorylation of NFs. The goal of this review is to provide an overview of the posttranslational modifications that occur in both normal and diseased axons. We review evidence that challenges the role of KSP phosphorylation as essential for radial growth and suggests an alternative role for NF phosphorylation in myelinated axons. Furthermore, we demonstrate that regulation of NF phosphorylation dynamics may be essential to avoiding NF accumulations. 1. Introduction The established role of neurofilaments (NFs) is to increase axonal diameter in myelinated fibers thereby increasing nerve conduction velocity [1]. NFs are composed of an N-terminal head, central rod, and C-terminal tail domain [2] (Figure 1). NFs are posttranslationally modified in all three of these functional domains [3–7]. NF phosphorylation, the most frequent posttranslational modification (PTM) and focus of our review, occurs primarily at conserved KSXXP motifs (KSP) located on the C-terminal tail domain of neurofilament heavy (NF-H) and medium (NF-M) [3–6]. However, phosphorylation of “non-KSP” serine residues within NF-M and neurofilament light (NF-L) amino terminal (N-terminal) head domain has been observed [7]. Transgenic [8] and gene-targeted [9] mouse lines expressing mutagenized NF phosphorylation sites have significantly advanced our understanding of the role of NF phosphorylation. For example, mice expressing a serine to aspartate mutation at position 55 of NF-L, NF-LS55D, displayed accumulations of phosphorylated NFs within cell bodies [8]. Furthermore, mice expressing serine to alanine mutations within the 7 identified KSP motifs of NF-M, , demonstrated an unaltered distribution of axonal
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