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

J. Biol. Chem., Vol. 283, Issue 11, 6979-6987, March 14, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/11/6979    most recent M710418200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawahara, K. Articles by Masliah, E. Search for Related Content PubMed PubMed Citation Articles by Kawahara, K. Articles by Masliah, E. Social Bookmarking                      What's this?

-Synuclein Aggregates Interfere with Parkin Solubility and Distribution

ROLE IN THE PATHOGENESIS OF PARKINSON DISEASE^*

Kohichi Kawahara, Makoto Hashimoto, Pazit Bar-On, Gilbert J. Ho, Leslie Crews, Hideya Mizuno, Edward Rockenstein, Syed Z. Imam^¶, and Eliezer Masliah¹

From the Departments of Neurosciences and Pathology, School of Medicine, University of California at San Diego, La Jolla, California 92039-0624 and the ^¶Departments of Medicine and Pharmacology and the Barshop Institute of Aging and Longevity Studies, University of Texas Health Science Center, San Antonio, Texas 78229-3900

Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and -synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. -Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether -synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-β resulted in accumulation of insoluble parkin and, to a lesser extent, -tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells -synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and -tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of -synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic -synuclein and parkin interactions in Parkinson disease.

Received for publication, December 21, 2007

^* This work was supported in part by National Institutes of Health Grants AG18440, AG10435, and AG22074 and the Mitsubishi Pharma Corp. 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: Dept. of Neurosciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Tel.: 858-534-6209; Fax: 858-534-6232; E-mail: emasliah{at}ucsd.edu.

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

This article has been cited by other articles:

				J. B. Rose, L. Crews, E. Rockenstein, A. Adame, M. Mante, L. B. Hersh, F. H. Gage, B. Spencer, R. Potkar, R. A. Marr, et al. Neuropeptide Y Fragments Derived from Neprilysin Processing Are Neuroprotective in a Transgenic Model of Alzheimer's Disease J. Neurosci., January 28, 2009; 29(4): 1115 - 1125. [Abstract] [Full Text] [PDF]