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J. Biol. Chem., Vol. 283, Issue 3, 1744-1753, January 18, 2008

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Missense Mutations in the Progranulin Gene Linked to Frontotemporal Lobar Degeneration with Ubiquitin-immunoreactive Inclusions Reduce Progranulin Production and Secretion^*

Sunita S. Shankaran¹, Anja Capell¹, Alexander T. Hruscha, Katrin Fellerer, Manuela Neumann, Bettina Schmid, and Christian Haass²

From the Munich Center for Integrated Protein Science and Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, and the Center for Neuropathology and Prion Research, Ludwig-Maximilians University, 80336 Munich, Germany

Loss of function mutations in progranulin cause tau-negative frontotemporal lobar degeneration with ubiquitin-positive inclusions. A major protein component of these inclusions is TDP-43, which becomes hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments, which apparently translocate from nuclei to the cytoplasm. Most progranulin mutations are nonsense mutations resulting in nonsense-mediated mRNA decay and consequently reduced progranulin protein levels. However, some missense mutations are described that occur within the signal sequence and mature progranulin. We now demonstrate that a progranulin mutation located within the signal sequence (PGRN A9D) results in cytoplasmic missorting with extremely low expression. In contrast, two other progranulin mutations (PGRN P248L and R432C) are expressed as immature proteins but are inefficiently transported through and partially degraded within the secretory pathway, resulting in a significantly reduced secretion. Thus apparently all progranulin mutations cause reduced protein expression or secretion, although by different cellular mechanisms. To investigate a putative relationship between reduced expression of progranulin and TDP-43 relocalization and deposition, we down-regulated progranulin in human cell lines and in zebrafish. Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease-characterizing C-terminal fragments could be observed.

Received for publication, June 21, 2007 , and in revised form, October 22, 2007.

^* This work was supported in part by the Gottfried Wilhelm Leibniz-Award of the Deutsche Forschungsgemeinschaft (to C. H.), the Hans & Ilse Breuer Foundation (to C. H.), and the Bundesministerium für Bildung und Forschung (to M. N. and C. H.). 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 Both authors contributed equally to this work.

² Supported by a Forschungsprofessur of the Ludwig-Maximilians University. To whom correspondence should be addressed: Adolf-Butenandt-Institute, Dept. of Biochemistry, Schillerstrasse 44, 80336 Munich, Germany. Tel.: 49-89-2180-75-471; Fax: 49-89-2180-75-415; E-mail: chaass{at}med.uni-muenchen.de.

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