Abstract
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 alpha-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 alpha-synuclein in inducing astrosenescence which may, in turn, increase the vulnerability of dopaminergic neurons to degeneration.
Original language | English |
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Article number | 103919 |
Number of pages | 13 |
Journal | Molecular and Cellular Neuroscience |
Volume | 128 |
Early online date | 1 Feb 2024 |
DOIs | |
Publication status | Published - 1 Mar 2024 |
Externally published | Yes |
Keywords
- alpha-Synuclein
- Astrosenescence
- Midbrain organoids
- CELLULAR SENESCENCE
- LAMIN B1
- MUTATION
- LOCUS