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Vol. 18, Issue 9, 3645-3655, September 2007

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Inhibition of Pin1 Reduces Glutamate-induced Perikaryal Accumulation of Phosphorylated Neurofilament-H in Neurons

Sashi Kesavapany^*,, Vyomesh Patel, Ya-Li Zheng^*, Tej K. Pareek, Mia Bjelogrlic^*, Wayne Albers^||, Niranjana Amin^*, Howard Jaffe^¶, J. Silvio Gutkind, Michael J. Strong^#, Philip Grant^*, and Harish C. Pant^*

*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, ONT, Canada N6A 5K8; and Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106

Submitted March 13, 2007; Revised June 8, 2007; Accepted July 3, 2007
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-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 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 small interfering RNA. Thus, isomerization of lys-ser-pro repeat 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 p-NF-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).

Abbreviations used: Cdk5, cyclin-dependent kinase 5; p-NF-H, phosphorylated neurofilament-H; Pin1, prolyl isomerase 1.

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