Abstract
Induced pluripotent stem cell-derived organoids offer an unprecedented access to complex human tissues that recapitulate features of architecture, composition and function of in vivo organs. In the context of Parkinson's Disease (PD), human midbrain organoids (hMO) are of significant interest, as they generate dopaminergic neurons expressing markers of Substantia Nigra identity, which are the most vulnerable to degeneration. Combined with genome editing approaches, hMO may thus constitute a valuable tool to dissect the genetic makeup of PD by revealing the effects of risk variants on pathological mechanisms in a representative cellular environment. Furthermore, the flexibility of organoid co-culture approaches may also enable the study of neuroinflammatory and neurovascular processes, as well as interactions with other brain regions that are also affected over the course of the disease. We here review existing protocols to generate hMO, how they have been used so far to model PD, address challenges inherent to organoid cultures, and discuss applicable strategies to dissect the molecular pathophysiology of the disease. Taken together, the research suggests that this technology represents a promising alternative to 2D in vitro models, which could significantly improve our understanding of PD and help accelerate therapeutic developments.
Highlights
Molecular Pathophysiology of Parkinson’s Disease Group, Paris Brain Institute (ICM), INSERM U, CNRS UMR 7225, Sorbonne University, Paris, France
This study found that the expression of candidate genes was exclusively enriched in neuronal cell types, a striking contrast with recent reports on the genetic architecture of Alzheimer’s Disease which heavily implicated peripheral and central nervous system (CNS) glial cell types [33]
Whether the observed phenotypes are due to developmental or agingrelated pathological mechanisms remains unclear, as limitations inherent to human induced pluripotent stem cell (hiPSC)-derived organoid cultures might for prevent the dissociation of such aspects
Summary
Much of our understanding of the pathological mechanisms of PD come from the study of relatively rare, high risk/monogenic forms of the disease. No significant association with other neuromodulator-producing neurons (serotonergic, noradrenergic, cholinergic) was revealed in these analyses, highlighting the centrality of DA and DA-associated networks in PD pathophysiology This result may be due to the fact that this study did not account for PD subtypes [21], which may be associated with alterations in different neurotransmitter systems [22,23,24,25,26,27]. Only a minor fraction of the disease’s heritability (16–36% depending on its prevalence) can be explained by the most recently identified risk loci [32], indicating that much of the “missing heritability” remains yet to be uncovered This may be partly achieved through better understanding of epistatic interactions and the functional annotation of the non-coding genome, in which a majority of the single nucleotide polymorphisms (SNPs) fall. As noncoding sequences tend to be less conserved between species, appropriate human models of the disease are required to expand our understanding of the molecular basis of PD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
