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Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg346
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Autophagy Regulates the Processing of Amino Terminal Huntingtin Fragments

Zheng-Hong Qin 1*, Yumei Wang 2, Kimberly B. Kegel 2, Aleksey Kazantsev 2, Barbara L. Apostol 3, Leslie Michels Thompson 3, Jennifer Yoder 2, Neil Aronin 4, and Marian DiFiglia 2

1 Laboratory of Cellular Neurobiology, Massachusetts General Hospital and Harvard Medical School, 16th Street, Bldg 114, Rm 2125, Charlestown, MA 02129
2 Laboratory of Cellular Neurobiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
3 Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697
4 Department of Medicine and Cell Biology, University of Massachusetts Medical Center, Worcester, MA 01655

* To whom correspondence should be addressed. E-mail: zhqin5{at}hotmail.com.


  Abstract

The N-terminus of mutant huntingtin (htt) has a polyglutamine expansion and forms neuronal aggregates in the brain of Huntington's disease patients. Htt expression in vitro activates autophagy, but it is unclear whether autophagic/lysosomal pathways process htt, especially N-terminal htt fragments. We explored the role of autophagy in htt processing in three cell lines, clonal striatal cells, PC12 cells, and rodent embryonic cells lacking cathepsin D. Blocking autophagy raised levels of exogenously expressed htt1-287 or 1-969, reduced cell viability, and increased the number of cells bearing mutant htt aggregates. Stimulating autophagy promoted htt degradation, including breakdown of caspase cleaved N-terminal htt fragments. Htt expression increased levels of the lysosomal enzyme cathepsin D by an autophagy-dependent pathway. Cells without cathepsin D accumulated more N-terminal htt fragments and cells with cathepsin D were more efficient in degrading wt htt than mutant htt in vitro. These results suggest that autophagy plays a critical role in the degradation of N-terminal htt. Altered processing of mutant htt by autophagy and cathepsin D may contribute to HD pathogenesis.


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