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In normal neurons, neurofilament (NF) proteins are phosphorylated in the axonal compartment. However, in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), NF proteins are aberrantly hyperphosphorylated within the cell bodies. The aberrant hyperphosphorylation of NF accumulations found in neurodegeneration could be attributable to either deregulation of proline-directed Ser/Thr kinase(s) activity or downregulation of protein phosphatase(s) activity. In this study, we found that protein phosphatase 2A (PP2A) expression is high in neuronal cell bodies and that inhibition of PP2A activity by okadaic acid (OA), microcystin LR (mLR), or fostriecin (Fos) leads to perikaryal hyperphosphorylation of NF. Peptidyl-prolyl isomerase Pin1 inhibits the dephosphorylation of NF by PP2A in vitro. In cortical neurons, Pin1 modulates the topographic phosphorylation of the proline-directed Ser/Thr residues within the tail domain of NF proteins by inhibiting the dephosphorylation by PP2A. Inhibition of Pin1 inhibits OA-induced aberrant perikaryal phosphorylation of NF. Treatment of cortical neurons with OA or Fos prevents the general anterograde transport of transfected green fluorescent protein-high-molecular-mass (NF-H) into axons caused by hyperphosphorylation of NF-H, and inhibition of Pin1 rescues this effect. Furthermore, inhibition of Pin1 inhibits the OA- or Fos-induced neuronal apoptosis. We show that OA-induced hyperphosphorylation of NF is a consequence of dephosphorylation of NF and is independent of c-Jun N-terminal protein kinase, extracellular signal-regulated kinase, and cyclin-dependent kinase-5 pathways. This study highlights a novel signaling role of PP2A by Pin1 and implicates Pin1 as a therapeutic target to reduce aberrant phosphorylation of NF proteins in neurodegenerative disorders such as AD, PD, and ALS.

Peptidyl-Prolyl Isomerase 1 Regulates Protein Phosphatase 2A-Mediated Topographic Phosphorylation of Neurofilament Proteins