Muwanigwa Mudiwa N, Modamio-Chamarro Jennifer, Antony Paul M A, Gomez-Giro Gemma, Krüger Rejko, Bolognin Silvia, Schwamborn Jens C
Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
Bioimaging Platform, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
Mol Cell Neurosci. 2024 Mar;128:103919. doi: 10.1016/j.mcn.2024.103919. Epub 2024 Feb 1.
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.
帕金森病（PD）是一种复杂的、进行性神经退行性疾病，其特征是中脑黑质致密部多巴胺能神经元丧失。尽管进行了广泛的研究，但PD神经退行性变之前的分子和细胞变化仍知之甚少。为了解决这个问题，我们在此描述了使用携带SNCA三倍体的患者特异性人类中脑类器官来研究多巴胺能变性的潜在机制。我们的中脑类器官模型概括了PD的关键病理特征，包括α-突触核蛋白的聚集和多巴胺能神经元的逐渐丧失。我们发现，这些病理特征与星形胶质细胞中衰老相关细胞表型的增加有关，包括核纤层缺陷、衰老相关异染色质灶的存在以及细胞周期停滞基因的上调。这些结果表明病理性α-突触核蛋白在诱导星形胶质细胞衰老中起作用，这反过来可能会增加多巴胺能神经元对变性的易感性。
