The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients

Seda Koyuncu, Isabel Saez, Hyun Ju Lee, Ricardo Gutierrez-Garcia, Wojciech Pokrzywa, Azra Fatima, Thorsten Hoppe and David Vilchez ()
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Seda Koyuncu: University of Cologne
Isabel Saez: University of Cologne
Hyun Ju Lee: University of Cologne
Ricardo Gutierrez-Garcia: University of Cologne
Wojciech Pokrzywa: University of Cologne
Azra Fatima: University of Cologne
Thorsten Hoppe: University of Cologne
David Vilchez: University of Cologne

Nature Communications, 2018, vol. 9, issue 1, 1-22

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05320-3

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