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Human Molecular Genetics Advance Access originally published online on November 29, 2006
Human Molecular Genetics 2007 16(1):61-77; doi:10.1093/hmg/ddl440
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis

Erica Rockabrand1,2, Natalia Slepko1, Antonello Pantalone5, Vidya N. Nukala6, Aleksey Kazantsev7, J. Lawrence Marsh8, Patrick G. Sullivan6, Joan S. Steffan1, Stefano L. Sensi3,5,9,* and Leslie Michels Thompson1,2,4,*

1 Department of Psychiatry and Human Behavior, 2 Department of Biological Chemistry, 3 Department of Neurology and 4 Department of Neurobiology and Behavior, University of California, Gillespie 2121, Irvine, CA 92697, USA, 5 Molecular Neurology Unit, Ce.S.I.–Center for Excellence on Aging, University ‘G. d'Annunzio’, Chieti 66013, Italy, 6 Spinal Cord and Brain Injury Research Center, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA, 7 MassGeneral Institute for Neurodegenerative Disease, MGH, Charlestown, MA 02139, USA, 8 Department of Developmental and Cell Biology, 4444 McGaugh Hall, University of California, Irvine, CA 92697, USA and 9 Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555-0539

* To whom correspondence should be addressed. Tel: +1 9498246756; Fax: +1 9498242577; Email: lmthomps{at}uci.edu (L.M.T.) also Tel: +39 0871 541544; Email: ssensi{at}uci.edu ( S.L.S.)

Received September 13, 2006; Accepted November 15, 2006

A truncated form of the Huntington's disease (HD) protein that contains the polyglutamine repeat, Httex1p, causes HD-like phenotypes in multiple model organisms. Molecular signatures of pathogenesis appear to involve distinct domains within this polypeptide. We studied the contribution of each domain, singly or in combination, to sub-cellular localization, aggregation and intracellular Ca2+ ([Ca2+]i) dynamics in cells. We demonstrate that sub-cellular localization is most strongly influenced by the first 17 amino acids, with this sequence critically controlling Httex1p mitochondrial localization and also promoting association with the endoplasmic reticulum (ER) and Golgi. This domain also enhances the formation of visible aggregates and together with the expanded polyQ repeat acutely disrupts [Ca2+]i levels in glutamate-challenged PC12 cells. Isolated cortical mitochondria incubated with Httex1p resulted in uncoupling and depolarization of these organelles, further supporting the idea that Httex1p-dependent mitochondrial dysfunction could be instrumental in promoting acute Ca2+ dyshomeostasis. Interestingly, neither mitochondrial nor ER associations seem to be required to promote long-term [Ca2+]i dyshomeostasis.


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