RT Journal Article
SR Electronic
T1 A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 291575
DO 10.1101/291575
A1 Claudia Lin-Kar Hung
A1 Tamara Maiuri
A1 Laura Erin Bowie
A1 Ryan Gotesman
A1 Susie Son
A1 Mina Falcone
A1 James Victor Giordano
A1 Virginia Mattis
A1 Trevor Lau
A1 Vickie Kwan
A1 Vanessa Wheeler
A1 Jonathan Schertzer
A1 Karun Singh
A1 Ray Truant
YR 2018
UL http://biorxiv.org/content/early/2018/04/12/291575.abstract
AB The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.