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LUHMES-derived 3D organoids as an enhanced platform for modelling dopaminergic neurodegeneration in Parkinson's disease
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DOI：10.3389/fmolb.2026.1807358.png)
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Abstract
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BackgroundParkinson’s disease (PD) research traditionally relies on animal models and two-dimensional (2D) culture models. These models fail to recapitulate the complex cellular architecture and network interactions that are possible with three-dimensional (3D) organoid models. While 3D models allow improved cell-cell interactions; spatial organization; and metabolic microenvironments; however; their utility for modelling dopaminergic neurodegeneration remains underexplored.MethodsWe developed and characterized 3D organoids from LUHMES cells which are human embryonic neuronal precursor cells and a well-established human dopaminergic neuronal cell line. We directly compare their responses to the mitochondrial toxin MPP+ against conventional 2D cultures. Functional readouts included cell viability; ATP production; dopaminergic marker expression (tyrosine hydroxylase; MAP2; β-III tubulin); reactive oxygen species (ROS) generation; electrophysiological activity via multi-electrode arrays (MEA); and calcium signalling dynamics.Results3D LUHMES organoids had 9-fold higher synapsin expression compared to 2D cultures; indicating enhanced synaptic maturity and network complexity. Following acute MPP+ exposure (0.25 mM; 24 h); 3D organoids were significantly more sensitive than 2D cultures; with greater reductions in cell viability (35% vs. 31%); ATP production (36% vs. 31%); and dopaminergic marker expression (TH: 60% reduction in both; MAP2: 70% vs. 54%; TUJ1: 62% vs. 20%). ROS production increased uniformly in 3D organoids (85% positive cells) compared to heterogeneous accumulation in 2D cultures (78% positive cells). Functional assessments revealed that 3D organoids displayed higher baseline electrophysiological activity that was sensitive to impairment following MPP+ treatment; spike amplitude; and calcium signalling responses to various stimuli (ATP; glutamate; GABA).ConclusionLUHMES-derived 3D organoids demonstrate greater physiological relevance for modelling PD-related dopaminergic neurodegeneration than 2D cultures. The enhanced sensitivity to mitochondrial toxins; combined with more sophisticated network architecture and functional properties; suggests this model is a valuable platform for mechanistic studies of neurodegeneration and preclinical drug screening. These findings also support the broader adoption of 3D culture systems in neurodegenerative disease research.
Keywords:
neurodegeneration
Parkinson’s disease
organoids
mitochondrial dysfunction
disease modelling
3D cell culture
LUHMES
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