Patient specific midbrain organoids model key hallmarks of Parkinson's disease.

Organoids show aggregation of α-synuclein and dopaminergic neuron loss.

Pathology in organoids is associated with a senescence-like phenotype in astrocytes.

Astrosenescence may contribute to neuronal vulnerability.

Parkinson's disease (PD) is a complex, progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Despite extensive research efforts, the molecular and cellular changes that precede neurodegeneration in PD are poorly understood. To address this, here we describe the use of patient specific human midbrain organoids harboring the SNCA triplication to investigate mechanisms underlying dopaminergic degeneration. Our midbrain organoid model recapitulates key pathological hallmarks of PD, including the aggregation of α-synuclein and the progressive loss of dopaminergic neurons. We found that these pathological hallmarks are associated with an increase in senescence associated cellular phenotypes in astrocytes including nuclear lamina defects, the presence of senescence associated heterochromatin foci, and the upregulation of cell cycle arrest genes. These results suggest a role of pathological α-synuclein in inducing astrosenescence which may, in turn, increase the vulnerability of dopaminergic neurons to degeneration.

α-Synuclein

Astrosenescence

Midbrain organoids

All original and processed data as well as scripts that support the findings of this study are publicly available at: doi:10.17881/zmmj-8z40.

© 2024 The Authors. Published by Elsevier Inc.