Unbiased profiling of Isogenic Huntington Disease hPSC-Derived CNS and peripheral cells reveals strong cell-type specificity of CAG length effects

Ooi, Jolene, Langley, Sarah ORCID: https://orcid.org/0000-0003-4419-476X, Xu, Xiaohong, Utami, Kagistia H., Sim, Bernice, Huang, Yihui, Harmston, Nathan P., Tay, Yi Lin, Ziaei, Amin, Zeng, Ruizhu, Low, Donovan, Aminkeng, Folefac, Sobata, Radoslaw M., Ginhoux, Florent, Petretto, Enrico and Pouladi, Mahmoud A. 2019. Unbiased profiling of Isogenic Huntington Disease hPSC-Derived CNS and peripheral cells reveals strong cell-type specificity of CAG length effects. Cell Reports 26 (9) , pp. 2494-2508. 10.1016/j.celrep.2019.02.008

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (5MB) | Preview

Abstract

In Huntington disease (HD), the analysis of tissue-specific CAG repeat length effects has been challenging, given the difficulty in obtaining relevant patient tissues with a broad range of CAG repeat lengths. We used genome editing to generate an allelic panel of isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying CAG repeat lengths in the first exon of HTT. Functional analyses in differentiated neural cells revealed CAG repeat length-related abnormalities in mitochondrial respiration and oxidative stress and enhanced susceptibility to DNA damage. To explore tissue-specific effects in HD, we differentiated the IsoHD panel into neural progenitor cells, neurons, hepatocytes, and muscle cells. Transcriptomic and proteomic analyses of the resultant cell types identified CAG repeat length-dependent and cell-type-specific molecular phenotypes. We anticipate that the IsoHD panel and transcriptomic and proteomic data will serve as a versatile, open-access platform to dissect the molecular factors contributing to HD pathogenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Cell Press
ISSN:	2211-1247
Date of First Compliant Deposit:	24 October 2023
Date of Acceptance:	1 February 2019
Last Modified:	24 Oct 2023 15:00
URI:	https://orca.cardiff.ac.uk/id/eprint/161887

Actions (repository staff only)

Edit Item