Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.

The aggregation of alpha-synuclein (aSyn) into intraneuronal inclusions of heterogeneous morphology, known as Lewy bodies (LBs), is a defining hallmark of Parkinson's disease (PD); yet, our understanding of the mechanisms underpinning their formation and heterogeneity remains incomplete. Here, we present a human isogenic induced pluripotent stem cell-derived dopaminergic neuron (iDA) model that faithfully recapitulates the diverse biochemical, morphological, and ultrastructural features of LB neuropathology. The iDA model accurately reproduces the temporal relationships between neuritic and cell-body aSyn pathology and recapitulates the proteome, posttranslational modifications, and morphological diversity of aSyn aggregates found in human PD tissue. Moreover, our work provides critical insight into how different pathways to aSyn fibrillization and the complex interaction between aSyn fibrils and membranous organelles shape the morphological diversity of LB-like inclusions. This model represents a versatile platform to investigate the mechanisms of pathology formation, maturation, and neuronal dysfunction and to develop diagnostics and therapeutics that account for the diversity of aSyn pathology in PD and related synucleinopathies.