HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 39, 26737-26747, September 26, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/39/26737    most recent M801633200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rudrabhatla, P. Articles by Pant, H. C. Search for Related Content PubMed PubMed Citation Articles by Rudrabhatla, P. Articles by Pant, H. C. Related Collections Related Webpages Social Bookmarking                      What's this?

F1000 Biology *Must Read* - FREE!

Pin1-dependent Prolyl Isomerization Modulates the Stress-induced Phosphorylation of High Molecular Weight Neurofilament Protein^*

Parvathi Rudrabhatla, Ya-Li Zheng, Niranjana D. Amin, Sashi Kesavapany, Wayne Albers, and Harish C. Pant¹

From the Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bethesda, Maryland 20892 and the Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, MD7 02-03, Singapore 117697

Aberrant phosphorylation of neuronal cytoskeletal proteins is a key pathological event in neurodegenerative disorders such as Alzheimer disease (AD) and amyotrophic lateral sclerosis, but the underlying mechanisms are still unclear. Previous studies have shown that Pin1, a peptidylprolyl cis/trans-isomerase, may be actively involved in the regulation of Tau hyperphosphorylation in AD. Here, we show that Pin1 modulates oxidative stress-induced NF-H phosphorylation. In an in vitro kinase assay, the addition of Pin1 substantially increased phosphorylation of NF-H KSP repeats by proline-directed kinases, Erk1/2, Cdk5/p35, and JNK3 in a concentration-dependent manner. In vivo, dominant-negative (DN) Pin1 and Pin1 small interfering RNA inhibited epidermal growth factor-induced NF-H phosphorylation. Because oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, we studied the role of Pin1 in stressed cortical neurons and HEK293 cells. Both hydrogen peroxide (H₂O₂) and heat stresses induce phosphorylation of NF-H in transfected HEK293 cells and primary cortical cultures. Knockdown of Pin1 by transfected Pin1 short interference RNA and DN-Pin1 rescues the effect of stress-induced NF-H phosphorylation. The H₂O₂ and heat shock induced perikaryal phospho-NF-H accumulations, and neuronal apoptosis was rescued by inhibition of Pin1 in cortical neurons. JNK3, a brain-specific JNK isoform, is activated under oxidative and heat stresses, and inhibition of Pin1 by Pin1 short interference RNA and DN-Pin1 inhibits this pathway. These results implicate Pin1 as a possible modulator of stress-induced NF-H phosphorylation as seen in neurodegenerative disorders like AD and amyotrophic lateral sclerosis. Thus, Pin1 may be a potential therapeutic target for these diseases.

Received for publication, February 28, 2008 , and in revised form, June 30, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Programs of the NINDS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cytoskeletal Protein Regulation Section, Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bldg. 49, Rm. 2A28, Bethesda, MD 20892. Tel.: 301-402-2124; Fax: 301-480-8280; E-mail: panth{at}ninds.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Webpages: