Meshorer's Lab: Progerin-Induced Transcriptional Changes in Huntington's Disease Human Pluripotent Stem Cell-Derived Neurons

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.