Hypokinetic and hyperkinetic movement disorders (i.e. Parkinson’s disease and dystonia respectively) are caused by opposite mechanisms in the basal ganglia. Those opposite movement disorders (reduced movements vs. excessive movements) are also characterized by opposite phenotypes regarding addiction-related behavior. Paradoxically, while those disorders seems to contrast each other, in some cases a mixed phenomenology is apparent: dystonia as a presenting sign of early Parkinson’s disease (PD), hinting for a shared pathophysiology. A large proportion of patients with either PD or dystonia were found in the last decades to have a monogenic cause, enabling to explore this shared pathophysiology. In my doctorate study, I will investigate this shared pathophysiology. To reach this aim, I am focusing on monogenic forms of PD and a specific monogenic form of dystonia, namely DYT-TOR1A secondary to a Glu303del mutation, mostly found in the Ashkenazi-Jewish population. Currently, in the first phase of my research, I am searching for possible genetic and epigenetic penetrance modifiers using DNA sequencing including long-read sequencing. This stage will be followed by both in-vitro models (mainly induced pluripotent stem cells differentiated into neurons from both affected patients and non-symptomatic carriers) and in-vivo models (transgenic zebrafish model). Later I plan to recruit PD patients with monogenic etiology, and eventually we plan to investigate our findings using animal brain models. Positive findings in this study will facilitate new therapy approaches to reduce disease burden among carriers of genes causing either PD or dystonia, and to expand our understanding of the pathophysiological mechanisms of addictions.

Supervisors: Prof. Tamir Ben-Hur and Prof. David Arkadir