Department of Neuroscience, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania.
Department of Neurology, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania.
Glia. 2019 Aug;67(8):1542-1557. doi: 10.1002/glia.23627. Epub 2019 Apr 26.
Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination of astrocytes in vitro exposes a novel vulnerability of presumably protected VTA DA neurons to the PD mimetic toxin MPP , as well as exacerbation of SN DA neuron vulnerability. Conversely, VTA astrocytes protected both VTA and SN DA neurons from MPP toxicity in a dose dependent manner, and this protection was mediated via a secreted molecule. RNAseq analysis of isolated VTA and SN astrocytes demonstrated a vast array of transcriptional differences between these two closely related populations demonstrating regional heterogeneity of midbrain astrocytes. We found that GDF15, a member of the TGFβ superfamily which is expressed 230-fold higher in VTA astrocytes than SN, recapitulates neuroprotection of both rat midbrain and iPSC-derived DA neurons, whereas its knockdown conversely diminished this effect. Neuroprotection was likely mediated through the GRFAL receptor expressed on DA neurons. Together; these results suggest that subregional differences in astrocytes underlie the selective degeneration or protection of DA neurons in PD.
帕金森病（PD）的特征是黑质致密部（SN）多巴胺（DA）神经元的选择性退化，而相邻的腹侧被盖区（VTA）相对幸免。这种选择性的机制尚未完全阐明。在这里，我们证明了亚区星形胶质细胞在保护 VTA DA 神经元中的重要作用。我们发现，体外消除星形胶质细胞会使假定受保护的 VTA DA 神经元对 PD 模拟毒素 MPP 暴露于新的脆弱性，以及 SN DA 神经元脆弱性的恶化。相反，VTA 星形胶质细胞以剂量依赖性的方式保护 VTA 和 SN DA 神经元免受 MPP 毒性，这种保护是通过分泌的分子介导的。分离的 VTA 和 SN 星形胶质细胞的 RNAseq 分析表明，这两个密切相关的群体之间存在大量转录差异，证明了中脑星形胶质细胞的区域异质性。我们发现，GDF15 是 TGFβ 超家族的成员，在 VTA 星形胶质细胞中的表达比 SN 高 230 倍，它可以重现大鼠中脑和 iPSC 衍生的 DA 神经元的神经保护作用，而其敲低则相反地减弱了这种作用。神经保护可能是通过 DA 神经元上表达的 GRFAL 受体介导的。综上所述，星形胶质细胞的亚区差异是 PD 中 DA 神经元选择性退化或保护的基础。
