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J. Biol. Chem., Vol. 283, Issue 20, 13771-13779, May 16, 2008

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Aberrant Folding of Pathogenic Parkin Mutants

AGGREGATION VERSUS DEGRADATION^*

From the Department of Biochemistry, Neurobiochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Schillerstrasse 44, Munich D-80336, Germany

Loss-of-function mutations in the Parkin gene (PARK2) are responsible for the majority of autosomal recessive Parkinson disease. A growing body of evidence indicates that misfolding and aggregation of Parkin is a major mechanism of Parkin inactivation, accounting for the loss-of-function phenotype of various pathogenic Parkin mutants. Remarkably, wild-type Parkin is also prone to misfolding under certain cellular conditions, suggesting a more general role of Parkin in the pathogenesis of Parkinson disease. We now show that misfolding of Parkin can lead to two phenotypes: the formation of detergent-insoluble, aggregated Parkin, or destabilization of Parkin resulting in an accelerated proteasomal degradation. By combining two pathogenic Parkin mutations, we could demonstrate that destabilization of Parkin is dominant over the formation of detergent-insoluble Parkin aggregates. Furthermore, a comparative analysis with HHARI, an E3 ubiquitin ligase with an RBR domain highly homologous to that of Parkin, revealed that folding of Parkin is specifically dependent on the integrity of the C-terminal domain, but not on the presence of a putative PDZ-binding motif at the extreme C terminus.

Received for publication, September 6, 2007 , and in revised form, March 14, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 596) and the Max Planck Society. 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: Tel.: 49-89-2180-75483; Fax: 49-89-2180-75415; E-mail: Konstanze.Winklhofer{at}med.uni-muenchen.de.

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