Dataset Information

A patient-derived cellular model for Huntington's disease reveals phenotypes at clinically relevant CAG lengths.

ABSTRACT: 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 adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios, and hypophosphorylated huntingtin protein. We additionally observed dysregulated reactive oxygen species (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 functions critical for huntingtin transcriptional regulation and genomic integrity.

SUBMITTER: Hung CL

PROVIDER: S-EPMC6249865 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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A patient-derived cellular model for Huntington's disease reveals phenotypes at clinically relevant CAG lengths.

Hung Claudia Lin-Kar CL Maiuri Tamara T Bowie Laura Erin LE Gotesman Ryan R Son Susie S Falcone Mina M Giordano James Victor JV Gillis Tammy T Mattis Virginia V Lau Trevor T Kwan Vickie V Wheeler Vanessa V Schertzer Jonathan J Singh Karun K Truant Ray R

Molecular biology of the cell 20180926 23

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 ...[more]

PMID: 30256717

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Dataset Information

A patient-derived cellular model for Huntington's disease reveals phenotypes at clinically relevant CAG lengths.

Publications

A patient-derived cellular model for Huntington's disease reveals phenotypes at clinically relevant CAG lengths.

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