Related Experiment Video
Updated: May 16, 2026
Monitoring Cell-to-cell Transmission of Prion-like Protein Aggregates in Drosophila Melanogaster
Published on: March 12, 2018
Pathogenic cellular phenotypes are germline transmissible in a transgenic primate model of Huntington's disease
Kittiphong Putkhao1, Jannet Kocerha, In-Ki Cho
1Yerkes National Primate Research Center, Atlanta, Georgia, USA.
Insights
Researchers achieved germline transmission of the Huntington
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- Huntington's Disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric deficits.
- Existing transgenic primate models exhibit motor symptoms but lack robust germline transmission of the causative gene.
- Developing a primate model with inherited mutant Huntingtin (HTT) is crucial for studying HD pathogenesis and therapeutics.
Purpose of the Study:
- To report the germline transmission of the mutant HTT gene in a transgenic primate model of Huntington's Disease.
- To derive and characterize Huntington's Disease monkey embryonic stem cells (rHD-ESCs) from germline-transmitted embryos.
- To establish a primate model that replicates key cellular and genetic features of human Huntington's Disease.
Main Methods:
- Utilized a previously established transgenic primate model carrying the mutant HTT gene with expanded CAG repeats.
- Produced embryos via in vitro fertilization using sperm from affected male monkeys.
- Derived and cultured rHD-ESCs, confirming inheritance of the mutant HTT and GFP transgenes.
Main Results:
- Successfully achieved germline transmission of the mutant HTT gene through gametes.
- Derived rHD-ESCs express the mutant HTT protein and form intranuclear inclusions, a hallmark of HD.
- Observed mosaicism in the polyglutamine (CAG) repeat region in sperm and derived ESCs, consistent with human HD observations.
Conclusions:
- This study establishes a milestone by confirming transgene inheritability and the development of HD phenotypes in derived rHD-ESCs.
- The rHD-ESC line provides a valuable platform for studying HD pathogenesis and developing novel biomarkers and therapeutics.
- This model offers unprecedented opportunities for preclinical testing of gene-targeted therapies in a primate system.
Abstract:
A transgenic primate model for Huntington's Disease (HD) first reported by our group that (HD monkeys) carry the mutant Huntingtin (HTT) gene with expanded polyglutamine (CAG) repeats and, develop chorea, dystonia, and other involuntary motor deficiencies similar to HD [ 1 ]. More recently, we have found that longitudinal magnetic resonance imaging of the HD monkey brain revealed significant atrophy in regions associated with cognitive deficits symptomatic in HD patients, providing the first animal model which replicates clinical phenotypes of diagnosed humans. Here we report germline transmission of the pathogenic mutant HTT in HD monkey by the production of embryos and subsequent derivation of HD monkey embryonic stem cells (rHD-ESCs) using HD monkey sperm. rHD-ESCs inherit mutant HTT and green fluorescent protein (GFP) genes through the gametes of HD monkey. rHD-ESCs express mutant HTT and form intranuclear inclusion, a classical cellular feature of HD. Notably, mosaicism of the pathogenic polyQ region in the sperm as well as derived ESCs were also observed, consistent with intraindividual and intergenerational reports of mosaic CAG repeats [ 2 , 3 ]and CAG expansion in HD patients [ 4-7 ]. The confirmation of transgene inheritability and development of pathogenic HD phenotype in derived rHD-ESCs reported in this study is a milestone in the pursuit of a transgenic primate model with inherited mutant HTT for development of novel disease biomarkers and therapeutics.
Related Concept Videos
01:21Huntington Disease l: Introduction
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...