Modeling early phenotypes of Parkinson's disease by age-induced midbrain-striatum assembloids [RNA-Seq]

Parkinson's disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson's disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson's disease. Overall design: RNA sequencing analysis of assembloids generated from a healthy male cell line (WT) and its isogenic genetically engineered line with the progerin transgene (PROG), under the control of the TetOn system. Assembloids from both cell lines were either untreated (UNTR) or treated with doxycycline (DOX). Doxycycline is used to induce the expression of the progerin transgene in the PROG assembloids.