Huntingtin's Roles in Fate Decision of GABAergic Neurons Derived from iPSCs of HD Patients

Abstract

Huntington's disease (HD) is a dominant inherited neurodegenerative disorder that is caused by mutation within the coding region of the huntingtin gene. The consequence of HD mutation is a massive brain degeneration characterized by the loss of GABAergic neurons from the brain. Stem cell-based therapies have emerged as powerful strategies for curing neurodegenerative diseases. One of the promising approaches to developing efficacious cell therapies for HD is to understand and command the molecular mechanisms that control neural stem cell differentiation into GABAergic neurons.Despite symptoms escalating during the adulthood, tangible evidences point to HD as an embryonic developmental disease. Thus, during embryonic neurogenesis different fractions of neural cells naturally die in controlled and programmed manners in order to establish correct brain structures. We have hypothesized that the biological influence of the mutant and wild types of huntingtin may play a pivotal role in affecting GABAergic neuron differentiation and survival, which ultimately contributes to neurological abnormalities of HD. Therefore, we propose to investigate the effect of huntingtin on GABAergic differentiation fate of induced pluripotent stem cells (iPSCs) derived from reprogramming skin fibroblast cells of adult HD patients (i.e., patient specific iPSC-based disease modeling in vitro, for which the PI Prof. Teng has expertise). Specifically, we focus on patterns of intracellular calcium concentration oscillations, a biological underpin directing pluripotent stem cell (e.g., embryonic stem cells) neuronal differentiation fate. Oscillations of intracellular calcium concentration was recently shown by Prof. Ulrich and Dr. Glaser (Fellow) to be an important molecular target to direct the differentiation of stem cells to GABAergic neurons. The novel approach will provide critical insight on the developmental feature of HD pathophysiology and help devise novel stem cells therapies, thus identifying new treatment windows to prevent and mitigate HD onset and subsequent clinical manifestations.