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ToxSci Advance Access originally published online on June 19, 2009
Toxicological Sciences 2009 111(1):100-108; doi:10.1093/toxsci/kfp132
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Published by Oxford University Press 2009.

Potential Role of {alpha}-Synuclein and Metallothionein in Lead-Induced Inclusion Body Formation

Peijun Zuo*, Wei Qu*, Ryan N. Cooper*, Robert A. Goyer*, Bhalchandra A. Diwan{dagger} and Michael P. Waalkes*,1

* Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 {dagger} Basic Research Program, SAIC-Frederick, Inc., NCI at Frederick, Maryland 21702

1 To whom correspondence should be addressed at Inorganic Carcinogenesis Section, NCI at NIEHS, PO Box 12233, Mail Drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709. Fax (919) 541-3970. E-mail: waalkes{at}niehs.nih.gov.

Received April 7, 2009; accepted June 4, 2009


  Abstract

Lead (Pb) produces aggresome-like inclusion bodies (IBs) in target cells as a toxic response. Our prior work shows metallothionein (MT) is required for this process. We used MT-I/II double knockout (MT-null) and parental wild-type (WT) cell lines to further explore the formation process of Pb-induced IBs. Unlike WT cells, MT-null cells did not form IBs after Pb exposure. Western blot of cytosol showed soluble MT protein in WT cells was lost during Pb exposure as IBs formed. Transfection of MT-I into MT-null cells allowed IBs formation after Pb exposure. Considering Pb-induced IBs may be like disease-related aggresomes, which often contain {alpha}-synuclein (Scna), we investigated Scna expression in cells capable (WT) and incapable (MT-null) of producing IBs after Pb exposure. Scna protein showed poor basal expression in MT-null cells. Pb exposure increased Scna expression only in WT cells. MT transfection increased Scna transcript to WT levels. In WT or MT-transfected MT-null cells, Pb-induced Scna expression rapidly increased and then decreased over 48 h as Pb-induced IBs were formed. A direct interaction between Scna and MT was confirmed ex vivo by antibody pulldown assay where the proteins coprecipitated with an antibody to MT. Pb exposure caused increased colocalization of MT and Scna proteins with time only in WT cells. In WT mice after chronic Pb exposure Scna was localized in renal cells containing forming IBs, whereas MT-null mice did not form IBs. Thus, Scna could be component of Pb-induced IBs and, with MT, may play a role in IBs formation.

Key Words: lead; inclusion bodies; {alpha}-synuclein; metallothionein; MT-null.


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