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  Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease

Hipp, M. S., Patel, C. N., Bersuker, K., Riley, B. E., Kaiser, S. E., Shaler, T. A., et al. (2012). Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease. J Cell Biol, 196(5), 573-87. doi:10.1083/jcb.201110093.

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 Creators:
Hipp, M. S.1, Author              
Patel, C. N.2, Author
Bersuker, K.2, Author
Riley, B. E.2, Author
Kaiser, S. E.2, Author
Shaler, T. A.2, Author
Brandeis, M.2, Author
Kopito, R. R.2, Author
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2External Organizations, ou_persistent22              

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Free keywords: Animals Cell Line Enzyme Stability Genes, Reporter HEK293 Cells Humans Huntington Disease/*physiopathology Mutation Nerve Tissue Proteins/genetics/*metabolism Nuclear Proteins/genetics/*metabolism Peptides/metabolism Proteasome Endopeptidase Complex/*metabolism *Proteasome Inhibitors Recombinant Fusion Proteins/genetics/metabolism Ubiquitin/genetics/*metabolism Ubiquitination
 Abstract: Pathognomonic accumulation of ubiquitin (Ub) conjugates in human neurodegenerative diseases, such as Huntington's disease, suggests that highly aggregated proteins interfere with 26S proteasome activity. In this paper, we examine possible mechanisms by which an N-terminal fragment of mutant huntingtin (htt; N-htt) inhibits 26S function. We show that ubiquitinated N-htt-whether aggregated or not-did not choke or clog the proteasome. Both Ub-dependent and Ub-independent proteasome reporters accumulated when the concentration of mutant N-htt exceeded a solubility threshold, indicating that stabilization of 26S substrates is not linked to impaired Ub conjugation. Above this solubility threshold, mutant N-htt was rapidly recruited to cytoplasmic inclusions that were initially devoid of Ub. Although synthetically polyubiquitinated N-htt competed with other Ub conjugates for access to the proteasome, the vast majority of mutant N-htt in cells was not Ub conjugated. Our data confirm that proteasomes are not directly impaired by aggregated N-terminal fragments of htt; instead, our data suggest that Ub accumulation is linked to impaired function of the cellular proteostasis network.

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 Dates: 2012
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: Other: 22371559
DOI: 10.1083/jcb.201110093
ISSN: 1540-8140 (Electronic) 0021-9525 (Linking)
URI: http://www.ncbi.nlm.nih.gov/pubmed/22371559
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Title: J Cell Biol
Source Genre: Journal
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Pages: - Volume / Issue: 196 (5) Sequence Number: - Start / End Page: 573 - 87 Identifier: -