Lewy Body-like Pathology and Loss of Dopaminergic Neurons in Midbrain Organoids Derived from Familial Parkinson's Disease Patient

卷:12

Article

关键词: PLURIPOTENT STEM-CELLS;    ALPHA-SYNUCLEIN;    PHOSPHORYLATION;    SH-SY5Y;    MODEL;    DIFFERENTIATION;    DUPLICATION;    MECHANISMS;    MITOPHAGY;    TOXICITY;   

DOI  :  10.3390/cells12040625

来源: SCIE

【 摘 要 】

Progressive accumulation of alpha-Synuclein (alpha Syn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson's disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of alpha Syn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. We demonstrated that hMBOs generated from induced pluripotent stem cells (hiPSCs), derived from a familial PD (fPD) patient carrying alpha Syn gene (SNCA) triplication accumulate pathological alpha Syn over time. These cytoplasmic inclusions spatially and morphologically resembled diverse stages of LB formation and were composed of key markers of LBs. Importantly, the progressive accumulation of pathological alpha Syn was paralleled by the loss of DA neurons and elevated apoptosis. The model developed in this study will complement the existing in vitro models of PD and will provide a unique platform to study the spatiotemporal events governing LB formation and their relation with neurodegeneration. Furthermore, this model will also be beneficial for in vitro screening and the development of therapeutic compounds.