Topographic Regulation of Neuronal Intermediate Filament Proteins by Phosphorylation: In Health and Disease

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Neurofilaments (NFs) belong to type 1 V family of intermediate filaments and are the most abundant proteins of the nervous system. Mammalian NF triplet proteins constitute three subunits, low molecular weight (NF-L), medium molecular weight (NF-M), and high molecular weight (NF-H) subunit proteins. The NF-M/H carboxy terminal tail domain has multiple KSP repeats (40≥100) depending upon species, the phosphorylation of which regulates axonal caliber and axonal transport. The NF tail domain contains phosphorylation sites for proline directed kinases such as mitogen activated protein kinases (MAPKs), cyclin dependent protein kinase 5 (Cdk5), c-Jun amino terminal kinase (JNKs), and glycogen synthase kinase-3 (GSK-3). The signaling cascades involved in NF phosphorylation like MAPKs and Cdk5 can also be affected by myelin associated glycoprotein (MAG). MAG activates the Erk1/2 and Cdk5 activities due to the glial/axon interaction and increases the proline directed Ser/Thr phosphorylation of C-terminal domain of NF-M/H. The NF phosphorylation is topographically regulated. In normal neurons, NFs are phosphorylated only in the axonal compartment. However, in degenerative neurons such as Alzheimer’s disease (AD), spinal cord motor neuron inclusions of amyotrophic lateral sclerosis (ALS), Lewy bodies of Parkinson’s disease (PD), and Pick’s disease neurofilament proteins are aberrantly phosphorylated in the cell bodies. Aberrant phosphorylation of NFs in neurodegeneration is either due to the deregulation of proline directed kinases such as MAPKs and Cdk5 or the downregulation of protein phosphatases such as protein phosphatase 2A (PP2A), calcineurin (PP2B), or both. Recently, studies from our laboratory have shown that peptidyl prolyl isomerase 1 (Pin1) stabilizes the NF phosphorylation in normal and stressed neurons. Pin1 selectively binds to the phosphorylated Ser/Thr-Pro residues and converts the cis isomers to the more stable trans isomers. The multiple SP repeats of NF-M/H are stabilized by Pin1 in a phosphorylation specific manner. Pin1 modulates the excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-M/H. Here, we have discussed the factors regulating the topographic phosphorylation of NFs in health and disease.