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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3231-3244
DOI: 10.1093/hmg/ddg346
© 2003 Oxford University Press

Autophagy regulates the processing of amino terminal huntingtin fragments

Zheng-Hong Qin1, Yumei Wang1, Kimberly B. Kegel1, Aleksey Kazantsev1, Barbara L. Apostol2, Leslie Michels Thompson2, Jennifer Yoder1, Neil Aronin3 and Marian DiFiglia1,*

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

Received May 13, 2003; Revised August 12, 2003; Accepted October 9, 2003

The N-terminus of mutant huntingtin (htt) has a polyglutamine expansion and forms neuronal aggregates in the brain of Huntington's disease (HD) 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.

* To whom correspondence should be addressed. Tel: +1 6172765762; Email: difiglia{at}helix.mgh.harvard.edu


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