Objective: The objectives of this study were (1) to create a human cell-based three-dimensional neural network that recapitulates the discrete somatic and axonal compartments of the nigrostriatal pathway; & (2) to use this testbed to explore potential mechanisms of neurodegeneration, such as cell-to-cell transmission of the alpha-synuclein (α-syn) protein.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of midbrain dopaminergic neurons. Accumulation of α-syn protein (pS129+) as fibrils and filamentous inclusion bodies within axons and neuronal somata is considered the hallmark of PD. Although the pathogenesis in extensively explored in various animal models of PD, the mechanism of pathophysiology in human brain is yet to be understood completely.

Method: Our Tissue Engineered Nigrostriatal Pathway (TE-NSP) is a living 3D microtissue construct that uniquely mimics the architecture of brain pathways with dopaminergic and medium spiny neurons (MSNs) spanned by long-projecting axonal tracts. To induce synucleinopathy, pre-formed fibrils (PFFs) of α-syn were injected in one neuronal population and cultured for another 14 days in vitro (DIV) before adding the second neuronal population.

Results: TE-NSPs demonstrated centimeter-long dopaminergic axonal tracts (up to ~1.8 cm long) and axonal-dendritic integration between the human dopaminergic neurons and MSNs. Immunocytochemistry using anti-α-syn-pS129 marker revealed synucleinopathy in 40-50% of the dopaminergic neurons and MSNs within the exposed TE-NSPs in comparison to less than 5% of the respective neuronal populations in unexposed controls. In addition, significantly lower mean intensity of tyrosine hydroxylase (TH) was observed in the pS129+ neurons, thereby reproducing one of the pathological phenotypes of human PD.

Conclusion: Recapitulating some aspects of neurodegeneration in human neurons is currently an unmet need, as animal models often fail to mimic the human pathophysiology. Therefore, a long-lived 3D TE-NSP model demonstrating transmission of α-syn pathology between two discrete neuronal populations holds great potential in understanding the mechanism of α-syn transmission, disease progression, and the underlying neurodegenerative events associated with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tissue-engineered-nigrostriatal-pathways-an-anatomically-inspired-model-of-synucleinopathy-in-human-neurons/