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Vol. 20, Issue 5, 1478-1492, March 1, 2009

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Mutant Huntingtin Impairs Post-Golgi Trafficking to Lysosomes by Delocalizing Optineurin/Rab8 Complex from the Golgi Apparatus

Daniel del Toro^*,, Jordi Alberch^*,, Francisco Lázaro-Diéguez^*,, Raquel Martín-Ibáñez^*,, Xavier Xifró^*,, Gustavo Egea^*,, and Josep M. Canals^*,

*Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, E-08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; and Institut de Nanotecnologia, Universitat de Barcelona, E-08036 Barcelona, Spain

Submitted July 16, 2008; Revised December 22, 2008; Accepted January 6, 2009
Monitoring Editor: Robert G. Parton

Huntingtin regulates post-Golgi trafficking of secreted proteins. Here, we studied the mechanism by which mutant huntingtin impairs this process. Colocalization studies and Western blot analysis of isolated Golgi membranes showed a reduction of huntingtin in the Golgi apparatus of cells expressing mutant huntingtin. These findings correlated with a decrease in the levels of optineurin and Rab8 in the Golgi apparatus that can be reverted by overexpression of full-length wild-type huntingtin. In addition, immunoprecipitation studies showed reduced interaction between mutant huntingtin and optineurin/Rab8. Cells expressing mutant huntingtin produced both an accumulation of clathrin adaptor complex 1 at the Golgi and an increase of clathrin-coated vesicles in the vicinity of Golgi cisternae as revealed by electron microscopy. Furthermore, inverse fluorescence recovery after photobleaching analysis for lysosomal-associated membrane protein-1 and mannose-6-phosphate receptor showed that the optineurin/Rab8-dependent post-Golgi trafficking to lysosomes was impaired in cells expressing mutant huntingtin or reducing huntingtin levels by small interfering RNA. Accordingly, these cells showed a lower content of cathepsin D in lysosomes, which led to an overall reduction of lysosomal activity. Together, our results indicate that mutant huntingtin perturbs post-Golgi trafficking to lysosomal compartments by delocalizing the optineurin/Rab8 complex, which, in turn, affects the lysosomal function.

Address correspondence to: Dr. Josep M. Canals (jmcanals{at}ub.edu)

Abbreviations used: AP-1, clathrin adaptor complex 1; CCV, clathrin-coated vesicle; GT, galactosyltransferase; htt, huntingtin; Lamp, lysosome-associated membrane protein; LcB, clathrin light chain B; MPR, mannose-6-phosphate receptor; TGN, trans-Golgi network; VSV-G, vesicular stomatitis virus glycoprotein.

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