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Cell Growth and Development

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

, , , , , , & show all
Pages 7554-7565 | Received 04 Jun 2003, Accepted 25 Jul 2003, Published online: 27 Mar 2023
 

Abstract

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.

ACKNOWLEDGMENTS

This work was supported by a Hereditary Disease Foundation grant to M.Y.S., by a Burroughs Wellcome Fund New Investigator Award in the Pharmacological Sciences and NIH R01 award GM60979 to B.W., by NSF DBI grant 0099705 to J.M.M. and B.W., and by a grant from the Huntington's Disease Society of America to Y.O.C.

We thank Gary Newnan for help with some experiments. We thank D. Drubin for the gift of the sla2 strain and J. Huibregtse for the gift of the Rsp5-HA strain.

Anatoli B. Meriin and Xiaoqian Zhang contributed equally to this work.

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