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J. Biol. Chem., Vol. 281, Issue 50, 38634-38643, December 15, 2006

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Synergistic Effects of the SAPK/JNK and the Proteasome Pathway on Glial Fibrillary Acidic Protein (GFAP) Accumulation in Alexander Disease^*

From the Department of Pathology and the Center for Neurobiology and Behavior, Columbia University, New York, New York 10032

Protein aggregates in astrocytes that contain glial fibrillary acidic protein (GFAP), small heat shock proteins, and ubiquitinated proteins are termed Rosenthal fibers and characterize Alexander disease, a leukodystrophy caused by heterozygous mutations in GFAP. The mechanisms responsible for the massive accumulation of GFAP in Alexander disease remain unclear. In this study, we show that overexpression of both wild type and R239C mutant human GFAP led to cytoplasmic inclusions. GFAP accumulation also led to a decrease of proteasome activity and an activation of the MLK2-JNK pathway. In turn, the expression of activated mixed lineage kinases (MLKs) induced JNK activation and increased GFAP accumulation, whereas blocking the JNK pathway decreased GFAP accumulation. Activated MLK also inhibited proteasome function. A direct inhibition of proteasome function pharmacologically further activated JNK. Our data suggest a synergistic interplay between the proteasome and the SAPK/JNK pathway in the context of GFAP accumulation. Feedback interactions among GFAP accumulation, SAPK/JNK activation, and proteasomal hypofunction cooperate to produce further protein accumulation and cellular stress responses.

Received for publication, May 23, 2006 , and in revised form, August 15, 2006.

^* This work was supported by National Institutes of Health Grant PO1NS42803. 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 Pathology, P&S Rm. 15-420, Columbia University College of P&S, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-3554; Fax: 212-305-4548; E-mail: jeg5{at}columbia.edu.

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