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The Journal of Neuroscience, December 6, 2006, 26(49):12748-12757; doi:10.1523/JNEUROSCI.3873-06.2006

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Neurobiology of Disease
Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism

Daniel del Toro,¹ Josep M. Canals,¹ Silvia Ginés,¹ Masami Kojima,^2,3 Gustavo Egea,¹ and Jordi Alberch¹

¹Departament de Biologia Cel·lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, 08036 Barcelona, Spain, ²Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka 563-8577, Japan, and ³Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, 332-0012, Japan

Correspondence should be addressed to Dr. Jordi Alberch, Departament de Biologia Cel·lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Carrer Casanova 143, E-08036 Barcelona, Spain. Email: alberch{at}ub.edu

Brain-derived neurotrophic factor (BDNF) polymorphism is associated with the pathophysiology of several neurodegenerative disorders, including Huntington's disease. In view of these data and the involvement of huntingtin in intracellular trafficking, we examined the intracellular transport and release of Val66Val BDNF (Val-BDNF) and Val66Met BDNF (Met-BDNF) in transfected striatal knock-in cells expressing wild-type or mutant full-length huntingtin. Colocalization studies with specific markers for endoplasmic reticulum showed no differences between the Val-BDNF and Met-BDNF and were not modified by mutant huntingtin. However, post-Golgi trafficking was altered by mutant huntingtin dependent on the BDNF form. Thus, fluorescence recovery after photobleaching (FRAP) and inverse FRAP analysis showed retention of Met-BDNF in the Golgi apparatus with respect to Val-BDNF in wild-type cells. Strikingly, mutant huntingtin diminished post-Golgi trafficking of Val-BDNF, whereas Met-BDNF was not modified. Accordingly, a reduction in the number of transport vesicles was only observed in mutant huntingtin cells transfected with Val-BDNF but not Met-BDNF. Moreover, mutant huntingtin severely affected the KCl-evoked release of Val-BDNF, although it had little effect on Met-BDNF regulated release. The constitutive release of Val-BDNF or Met-BDNF in mutant cells was only slightly reduced. Interestingly, mutant huntingtin only perturbed post-Golgi trafficking of proteins that follow the regulated secretory pathway (epidermal growth factor receptor or atrial natriuretic factor), whereas it did not change those that follow the constitutive pathway (p75^NTR).

We conclude that mutant huntingtin differently affects intracellular transport and release of Val-BDNF and Met-BDNF. In addition, our findings reveal a new role for huntingtin in the regulation of the post-Golgi trafficking of the regulated secretory pathway.

Key words: Huntington's disease; neurotrophin; vesicular transport; trans-Golgi network; p75; EGFR

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Received April 20, 2006; revised Oct. 25, 2006; accepted Oct. 26, 2006.

Correspondence should be addressed to Dr. Jordi Alberch, Departament de Biologia Cel·lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Carrer Casanova 143, E-08036 Barcelona, Spain. Email: alberch{at}ub.edu

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