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

J. Biol. Chem., Vol. 281, Issue 43, 32148-32155, October 27, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/43/32148    most recent M605965200v1 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 Wislet-Gendebien, S. Articles by Tandon, A. Search for Related Content PubMed PubMed Citation Articles by Wislet-Gendebien, S. Articles by Tandon, A. Social Bookmarking                      What's this?

Cytosolic Proteins Regulate -Synuclein Dissociation from Presynaptic Membranes^*

From the Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada

Intracellular accumulation of insoluble -synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of -synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of -synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of -synuclein to self-assemble into fibrils. In addition to the -helical form that is peripherally-attached to vesicles, a substantial portion of -synuclein is freely diffusible in the cytoplasm. The mechanisms controlling -synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble -synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate -synuclein membrane interactions. Here we reveal that dissociation of membrane-bound -synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent -synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate -synuclein interactions with intracellular membranes. Importantly, our finding that -synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence -synuclein aggregation.

Received for publication, June 22, 2006 , and in revised form, August 3, 2006.

^* This work was supported by operating grants (to A. T.) from the Canadian Institute of Health Research (CIHR) and the Parkinson Society of Canada. 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 Postdoctoral support was provided by the Leon Frederick Foundation and the Journal of Cell Science travel grant.

² To whom correspondence should be addressed: Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada. Tel.: 416-978-8880; Fax: 416-978-1878; E-mail: a.tandon{at}utoronto.ca.

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