Universität zu Köln

Koyuncu, Seda, Saez, Isabel, Lee, Hyun Ju, Gutierrez-Garcia, Ricardo, Pokrzywa, Wojciech ORCID: 0000-0002-5110-4462, Fatima, Azra, Hoppe, Thorsten ORCID: 0000-0002-4734-9352 and Vilchez, David ORCID: 0000-0002-0801-0743 (2018). The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington's disease patients. Nat. Commun., 9. BERLIN: NATURE RESEARCH. ISSN 2041-1723

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Abstract

Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington's disease (HD). Here we show that proteasome activity determines HTT levels, preventing polyQ-expanded aggregation in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit high levels of UBR5, a ubiquitin ligase required for proteasomal degradation of both normal and mutant HTT. Conversely, loss of UBR5 increases HTT levels and triggers polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens polyQ-expanded aggregation and neurotoxicity in invertebrate models. Notably, UBR5 overexpression induces polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD-cell models. Besides HTT levels, intrinsic enhanced UBR5 expression determines global proteostasis of iPSCs preventing the aggregation of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a modulator of super-vigilant proteostasis of iPSCs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koyuncu, Seda UNSPECIFIED UNSPECIFIED UNSPECIFIED Saez, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Hyun Ju UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutierrez-Garcia, Ricardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Pokrzywa, Wojciech UNSPECIFIED orcid.org/0000-0002-5110-4462 UNSPECIFIED Fatima, Azra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED Vilchez, David UNSPECIFIED orcid.org/0000-0002-0801-0743 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-179565
DOI:	10.1038/s41467-018-05320-3
Journal or Publication Title:	Nat. Commun.
Volume:	9
Date:	2018
Publisher:	NATURE RESEARCH
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MACHADO-JOSEPH-DISEASE; POLYGLUTAMINE PROTEINS; STRESS GRANULES; CAG EXPANSIONS; IN-VIVO; AGGREGATION; GENE; MECHANISMS; TOXICITY; FUS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17956