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. 2006 May;22(2):346-56.
doi: 10.1016/j.nbd.2005.11.012. Epub 2006 Jan 19.

Lysosomal proteases are involved in generation of N-terminal huntingtin fragments

Yun J Kim  1 , Ellen Sapp, Benjamin G Cuiffo, Lindsay Sobin, Jennifer Yoder, Kimberly B Kegel, Zheng-Hong Qin, Peter Detloff, Neil Aronin, Marian DiFiglia
Affiliations

Lysosomal proteases are involved in generation of N-terminal huntingtin fragments

Yun J Kim et al. Neurobiol Dis. 2006 May.

Abstract

N-terminal mutant huntingtin (N-mhtt) fragments form inclusions and cause cell death in vitro. Mutant htt expression stimulates autophagy and increases levels of lysosomal proteases. Here, we show that lysosomal proteases, cathepsins D, B and L, affected mhtt processing and levels of cleavage products (cp) known as A and B, which form inclusions. Adding inhibitors of cathepsin D, B and L to clonal striatal cells reduced mhtt, especially mhtt fragment cp A. Mutant htt fully degraded in cathepsin-L-treated lysates but formed stable N-mhtt fragments upon exposure to cathepsin D. Mutagenesis analysis of htt cDNA suggested that cathepsin D and the protease for cp A may cleave htt in the same region. Brain lysates from HD knock-in mice expressed N-mhtt fragments that accumulated with cathepsin D treatment and declined with aspartyl protease inhibition. Findings implicate lysosomal proteases in formation of N-mhtt fragments and clearance of mhtt.

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