Huntington’s disease (HD) is a neurodegenerative late-onset genetic disorder. In spite of the availability of many animal models, there is still no cure for this disease. In this study we established a convenient in-vitro human model system to study HD using human embryonic stem cells (hESCs) and patient-derived human induced pluripotent stem cells (iPSCs) lines. The ~45 days differentiation protocol produces electrophysiologically active striatal GABAergic post-mitotic neurons, which are the most vulnerable in HD. However, these neurons, as in most stem cell differentiation protocols, are in a state, which is equivalent to newly-born neurons and therefore lack this important disease-related component. We therefore accelerated the aging of the neurons in culture by forcing the cells to express Progerin, a mutated protein which causes the premature aging Hutchinson Gilford Progeria Syndrome. We show that aging the neurons aggravates the otherwise subtle transcriptional changes between wild type and HD neurons.
Paper of the month
Meshorer's Lab: Progerin-Induced Transcriptional Changes in Huntington's Disease Human Pluripotent Stem Cell-Derived Neurons
Mol Neurobiol. 2020 Mar;57(3):1768-1777. (2019)