Alpha-synuclein pathology is associated with astrocyte senescence in a midbrain organoid model of familial Parkinson's disease

Mudiwa N. Muwanigwa, Jennifer Modamio-Chamarro, Paul M.A. Antony, Gemma Gomez-Giro, Rejko Krüger, Silvia Bolognin, Jens C. Schwamborn*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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 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.

Original languageEnglish
Article number103919
JournalMolecular and Cellular Neurosciences
Volume128
Early online date1 Feb 2024
DOIs
Publication statusPublished - Mar 2024
Externally publishedYes

Keywords

  • Astrosenescence
  • Midbrain organoids
  • α-Synuclein

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