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

Mark S. Hipp, Chetan N. Patel, Kirill Bersuker, Brigit E. Riley, Stephen E. Kaiser, Thomas A. Shaler, Michael Brandeis, Ron R. Kopito*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


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.

Original languageAmerican English
Pages (from-to)573-587
Number of pages15
JournalJournal of Cell Biology
Issue number5
StatePublished - 2012


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