Abstract
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.
Highlights
The established role of neurofilaments (NFs) is to increase axonal diameter in myelinated fibers thereby increasing nerve conduction velocity [1]
When taken together with the results obtained from NF-MTailΔ mice, these results suggested that the C-terminus of neurofilament medium (NF-M) mediated radial growth by a mechanism that did not require KSXXP motifs (KSP) phosphorylation
A series of recent analyses conducted on genetically modified mice has provided evidence against the role of NF phosphorylation in radial growth
Summary
The established role of neurofilaments (NFs) is to increase axonal diameter in myelinated fibers thereby increasing nerve conduction velocity [1]. 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) [3,4,5,6]. Phosphorylation of “non-KSP” serine residues within NFM and neurofilament light (NF-L) amino terminal (Nterminal) head domain has been observed [7]. Mice expressing a serine to aspartate mutation at position 55 of NF-L, NF-LS55D, displayed accumulations of phosphorylated NFs within cell bodies [8]. Mice expressing serine to alanine mutations within the 7 identified KSP motifs of NF-M, NF-MS → A, demonstrated an unaltered distribution of axonal diameters [9].
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