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.
Citations
Dec 4, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Swati NaphadeLisa M Ellerby
May 30, 2020·Current Protocols in Human Genetics·Tuyana MalankhanovaAnastasia Malakhova
Mar 19, 2020·International Journal of Molecular Sciences·Magdalena DabrowskaMarta Olejniczak
Sep 9, 2020·Human Molecular Genetics·Galen E B WrightMichael R Hayden
Jun 6, 2020·Antioxidants & Redox Signaling·Lígia Fão, Ana Cristina Rego
Oct 28, 2020·Cellular and Molecular Neurobiology·Akanksha BaharaniDarrell D Mousseau
Nov 11, 2020·International Journal of Molecular Sciences·Manuela Bozzi, Francesca Sciandra
Dec 22, 2020·Experimental Neurology·Lang HeHong Jiang
Feb 20, 2021·Frontiers in Cell and Developmental Biology·Vladimir A VigontElena V Kaznacheyeva
Feb 22, 2021·Journal of Assisted Reproduction and Genetics·Sujittra KhampangAnthony W S Chan
Feb 29, 2020·Stem Cell Reports·Charlene Smith-GeaterLeslie M Thompson
Apr 22, 2021·Journal of Neuroscience Research·Margarida BeatrizAna Cristina Carvalho Rego
Apr 21, 2021·Journal of Neuroinflammation·Grace C O'ReganRalph Andre
Jul 2, 2021·Frontiers in Molecular Neuroscience·Xiaolin ZhuHubin Duan
Oct 27, 2020·Current Topics in Medicinal Chemistry·Josep GarciaMeritxell Teixidó
Jul 8, 2021·Cell Reports·Abdellatif BenraissSteven A Goldman
Aug 15, 2021·Neurobiology of Disease·Fanny L LemariéMichael R Hayden
Sep 27, 2020·Cell Death & Disease·Xiaohong XuMahmoud A Pouladi
Oct 19, 2021·Frontiers in Cellular Neuroscience·Jenny LangeSarah J Tabrizi
Oct 30, 2021·Frontiers in Genome Editing·Amy McTagueManju A Kurian
Nov 2, 2021·Frontiers in Genetics·Bimala MallaFerah Yildirim