Neurofilament phosphorylation and their proline-directed kinases in health and disease

The intermediate filaments called neurofilaments (NFs) are the main cytoskeleton elements in neurons. They are mainly present in the adult axonal cytoskeleton, where they are extensively phosphorylated and their phosphorylation status is pivotal for their properties and functions. Specific phosphorylation of the C-terminal domains of the large NF subunits has been implicated in radial axonal growth, NF bundling, and NF axonal transport. Many kinases and phosphatases are involved in regulating the NF phosphorylation status, and this complex interplay is of growing interest as hyperphosphorylation of NFs is a hallmark of several neurodegenerative diseases. In this review, we focus on the in vivo relevance of C-tail phosphorylation of the large NF subunits and give an overview of the kinases and phosphatases involved in regulating the phosphorylation status of the NFs.