[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
MUWANIGWA, Mudiwa Nathasia ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Developmental and Cellular Biology > Team Jens Christian SCHWAMBORN
Modamio-Chamarro, Jennifer; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
Gomez-Giro, Gemma; Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
Krüger, Rejko; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg
Medical Research and Materiel Command Fonds National de la Recherche US Army Medical Research and Materiel Command U.S. Army
Funding text :
The work leading to this manuscript was supported through funding to JCS's lab: Fonds National de la Recherche Luxembourg ( PRIDE17/12244779/PARK-QC ; CORE C21/DM/15839823 ; BRIDGES18/BM/12719664_MOTASYN ; INTER/FWF/19/14117540/PDage ). The U.S. Army Medical Research and Materiel Command endorsed by the U.S. Army through the Parkinson's Research Program Investigator-Initiated Research Award under Award No. W81XWH-17-PRP-IIRA . Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the U.S. Army. SB received funding from the Fonds National de la Recherche Luxembourg ( Core C21/DM/15839823 ).
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