Modeling early phenotypes of Parkinson's disease by age-induced midbrain-striatum assembloids.

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.
Competing Interests: Competing interests: J.C.S. is a co-inventor on a patent covering the generation of the here-described midbrain organoids (WO2017060884A1). Furthermore, J.C.S. is a co-founder and shareholder of the company OrganoTherapeutics which makes use of midbrain organoid technology. The other authors declare no competing interests. Ethical approval: Ethics Review Panel (ERP) of the University of Luxembourg and the national Luxembourgish research ethics committee (CNER, Comité National d’Ethique de Recherche) have approved the work with induced pluripotent stem cells (iPSCs). CNER No. 201901/01; ivPD.
(© 2024. The Author(s).)