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A more recent version of this article appeared on September 1, 2007
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Submitted on March 13, 2007
Revised on June 8, 2007
Accepted on July 3, 2007
*Cytoskeletal Protein Regulation Section, ||Section on Enzyme Chemistry, ¶Protein and Peptide Facility, National Institute of Neurological Disorders and Stroke, and Laboratory of Oral and Pharyngeal Cancer, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; #Robarts Research Institute, London, Ontario, Canada N6A 5K8; Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106
Monitoring Editor: M. Bishr Omary
Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NFH) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration we studied glutamate-stressed neurons which displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin 1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 siRNA. Thus, isomerization of lys-ser-prorepeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of pNF-H.
Present address: Yong Loo Lin School of Medicine, Department of Biochemistry, National University of Singapore, 8 Medical Drive, MD7 #02-03, Singapore 117597.
Address correspondence to:
Harish C. Pant (panth{at}ninds.nih.gov)
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