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Inhibition of Usp14 Stimulates the Proteolytic Degradation and Clearance of Misfolded Proteins Associated with Neurodegenerative Diseases
Author(s) -
Villella Adriana T,
Malhotra Jyoti,
Bhalla Akhil,
Nokes Eva,
HurtadoLorenzo Andres,
Calamani Barbara,
Soper James,
Gao Benbo,
Giuliano Kenneth,
Hafiz Mohmmad,
Foley Megan,
Tait Brad,
Haeberlein Markus,
Saha Anjanabha,
Reinhart Peter,
King Randall,
Finley Daniel,
Lo Donald,
Garza Dan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb131
Subject(s) - proteostasis , proteasome , aggresome , ubiquitin , microbiology and biotechnology , deubiquitinating enzyme , induced pluripotent stem cell , protein degradation , protein aggregation , protein folding , mg132 , proteolysis , biology , chemistry , biochemistry , proteasome inhibitor , enzyme , gene , embryonic stem cell
Proteasomes play a key role in the degradation of polyubiquitinated proteins. The proteasome‐associated de‐ubiquitinating enzyme (DUB) Usp14 slows the degradation of some ubiquitin‐protein conjugates by removing ubiquitin chains prior to substrate degradation. We have carried out proof‐of‐concept (PoC) experiments demonstrating that siRNA‐mediated knockdown of Usp14 leads to reductions in α‐synuclein levels in HEK293 cells, induced pluripotent human stem cell‐derived neurons (iPS neurons) and rat brain slices. Compound‐mediated inhibition of Usp14 using selective inhibitors was also shown to reduce α‐synuclein protein levels in both iPS neurons and rat brain slices. Further, these results have been extended to other disease‐related client proteins. These results suggest Usp14 inhibition as a new therapeutic approach for the treatment of protein aggregation diseases through proteasome‐mediated clearance of disease‐associated proteins. The use of small molecules to manipulate proteasomal activity is one of several strategies being used at Proteostasis Therapeutics to treat a number of neurodegenerative and orphan diseases through modulation of the proteostasis network responsible for the folding, trafficking, and degradation of misfolded and aggregated proteins.