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Age-induced midbrain-striatum assembloid models early phenotypes of Parkinson’s disease [scRNA-Seq]

ABSTRACT: Parkinson’s disease, one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics necessary for the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease’s phenotypes. Here we present a method for the generation of a midbrain-striatum assembloid model with inducible aging. Aging is induced by expression of progerin. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging phenotypes that lead to early phenotypes of Parkinson’s disease. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241631 | GEO | 2023/10/28

REPOSITORIES: GEO

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Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease [RNA-Seq]

Project description:Parkinson's disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease's phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

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In vitro Modeling of the Human Dopaminergic System using spatially arranged ventral Midbrain-Striatum-Cortex Assembloids [Smartseq]

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Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features. Induced pluripotent stem cell-derived midbrain dopamine neurons from a young and old donor overexpressing either GFP or Progerin.

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Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease [RNA-Seq]

Project description:Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease [RNA-Seq]

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