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Molecular and Cellular Biology, November 2003, p. 7554-7565, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7554-7565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Aggregation of Expanded Polyglutamine Domain in Yeast Leads to Defects in Endocytosis

Anatoli B. Meriin,1 Xiaoqian Zhang,1 Nicholas B. Miliaras,2 Alex Kazantsev,3 Yury O. Chernoff,4 J. Michael McCaffery,2,5 Beverly Wendland,2 and Michael Y. Sherman1*

Department of Biochemistry, Boston University School of Medicine,1 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts,3 Department of Biology,2 The Integrated Imaging Center, The Johns Hopkins University, Baltimore, Maryland,5 School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia4

Received 4 June 2003/ Returned for modification 15 July 2003/ Accepted 25 July 2003

The role of aggregation of abnormal proteins in cellular toxicity is of general importance for understanding many neurological disorders. Here, using a yeast model, we demonstrate that mutations in many proteins involved in endocytosis and actin function dramatically enhance the toxic effect of polypeptides with an expanded polyglutamine (polyQ) domain. This enhanced cytotoxicity required polyQ aggregation and was dependent on the yeast protein Rnq1 in its prion form. In wild-type cells, expression of expanded polyQ followed by its aggregation led to specific and acute inhibition of endocytosis, which preceded growth inhibition. Some components of the endocytic machinery were efficiently recruited into the polyQ aggregates. Furthermore, in cells with polyQ aggregates, cortical actin patches were delocalized and actin was recruited into the polyQ aggregates. Aggregation of polyQ in mammalian HEK293 cells also led to defects in endocytosis. Therefore, it appears that inhibition of endocytosis is a direct consequence of polyQ aggregation and could significantly contribute to cytotoxicity.

* Corresponding author. Mailing address: Boston University School of Medicine, Department of Biochemistry, K323, 715 Albany St., Boston, MA 02118. Phone: (617) 638-5971. Fax: (617) 638-5339. E-mail: sherman{at}biochem.bumc.bu.edu.

Molecular and Cellular Biology, November 2003, p. 7554-7565, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7554-7565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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