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Stem Cell Research Leads to Insights Into How Huntington’s Disease Develops

Characterization of neurodevelopmental abnormalities in cultures from Huntington’s disease patients may help to understand juvenile HD and pave the way for developing future treatment pathways, according to a novel study published in JHD

October 21, 2019
Amsterdam, NL – Huntington's disease (HD) is a fatal hereditary disease for which there is no cure. A novel study from Cedars-Sinai Medical Center, Los Angeles, USA, using pluripotent stem cells advances understanding of how the disease develops and may help pave the way for identifying pathways for future treatments. Results are published in the Journal of Huntington’s Disease.

HD is caused by an expansion of a repeating “CAG” triplet series in the huntingtin (HTT) gene, which results in a protein with an abnormally long polyglutamine sequence. Individuals with between 36–40 CAG repeats have a less severe form of HD with later onset and slower progression. HD is traditionally considered as an adult onset neurodegenerative disorder, but a small number of patients carry more than 60 CAG repeats, which causes a severe form with juvenile onset. The present study was designed to explore the potential neurodevelopmental aspects of the disease.

Investigators used induced pluripotent stem cells (iPSC) using five cell lines generated from juvenile HD and five controls to model the development of the region of the brain most affected by HD. Lead investigator Virginia B. Mattis, PhD, with The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles when the study was conducted, explained: “Before the discovery of embryonic stem cells, only post-mortem human brain tissues were available for us to study, limiting investigation of the developmental pathophysiology of the disease. However, with the use of iPSC, somatic cells reprogrammed to embryonic state, means it is possible to focus on the origins of HD in human brain tissues generated in vitro.”

Using immunocytochemistry and stereological quantification, the researchers studied the differentiation of human iPSCs towards striatal fate and characterization. There was a distinct delay in development of juvenile onset HD iPSC characterized by the increased percentage of nestin-expressing neural progenitor cells at 42 days of differentiation. Nestin is a neural progenitor marker that is expressed throughout the development of the central nervous system. A partial reversal of this phenotype was demonstrated using small molecules or anti-sense oligonucleotides.

“This study provides evidence to support the hypothesis of delayed development phenotype in the juvenile onset HD patient striatum,” noted Dr. Mattis. “After differentiating towards striatal fate, juvenile HD cultures showed a significantly higher percentage of nestin positive cells. HTT knockdown throughout the course of differentiation can reverse the phenotype. Inhibition of canonical Notch pathway (DAPT) reversed the elevated nestin phenotype. This approach of disease modelling presents an ideal opportunity to study the early disease onset and its progression and can provide insight to understanding of the developmental aspects of juvenile HD. Better understanding the origins of disease could aid in targeting pathways of therapeutic intervention in the future.”

HD is a fatal genetic neurodegenerative disease characterized by atrophy of certain regions of the brain. It causes the progressive breakdown of nerve cells in the brain. HD patients experience behavioral changes and uncontrolled movements. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, and unsteady gait and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients usually survive 10–20 years after diagnosis.


Full open access study:Characterization of Neurodevelopmental Abnormalities in iPSC-Derived Striatal Cultures from Patients with Huntington’s Disease” by Pranav P. Mathkar, Divya Suresh, James Dunn, Colton M. Tom, and Virginia B. Mattis (DOI 10.3233/JHD-180333) appears in the Journal of Huntington’s Disease, Volume 8, Issue 3, published by IOS Press. This article is openly available at:

Pranav P. Mathkar, Divya Suresh, and James Dunnwere were funded by the CIRM Bridges program. 

Contact Diana Murray, IOS Press (+1 718-640-5678 or for additional information. Journalists who wish to interview the authors should contact Virginia B. Mattis ( Dr. Mattis is currently affiliated with Fujifilm Cellular Dynamics, Inc., Madison, WI, USA.

About the Journal of Huntington’s Disease
The Journal of Huntington’s Disease (JHD) is an international multidisciplinary journal to facilitate progress in understanding the genetics, molecular correlates, pathogenesis, pharmacology, diagnosis and treatment of Huntington’s disease and related disorders. The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. JHD is dedicated to providing an open forum for original research in basic science, translational research, and clinical medicine that will expedite our fundamental understanding and improve treatment of Huntington’s disease and related disorders.

About IOS Press
IOS Press is headquartered in Amsterdam with satellite offices in the USA, Germany, India and China and serves the information needs of scientific and medical communities worldwide. IOS Press now publishes more than 80 international peer-reviewed journals and about 75 book titles each year on subjects ranging from computer science, artificial intelligence, and engineering to medicine, neuroscience, and cancer research.