Midbrain organoids as next-generation models for Parkinson's disease: From pathogenesis to therapeutic discovery

Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and pathological aggregation of α-synuclein. Traditional two-dimensional (2D) cell cultures and animal models have provided valuable insights but fail to recapitulate the cellular architecture and pathophysiology of the human midbrain. Three-dimensional (3D) midbrain organoids self-organize into neural structures that mimic key aspects of human midbrain development and disease pathology. This review examines midbrain organoid-based PD modeling through a concept-driven lens, addressing five questions: (i) Which aspects of PD can organoids model? (ii) How are technological advances reshaping the field? (iii) How do organoids complement existing model systems? (iv) What are the current limitations, and how can they be addressed? (v) What is the path toward clinical translation? Organoids reliably reproduce mitochondrial and lysosomal dysfunction and, in SNCA triplication models, α-synuclein accumulation, but seldom progressive neurodegeneration or mature Lewy pathology. By distinguishing established findings from emerging technologies and providing a realistic assessment of current limitations, this review offers a framework for prioritizing organoid applications in PD research and translation.