Wang Liqun, Hagemann Tracy L, Kalwa Hermann, Michel Thomas, Messing Albee, Feany Mel B
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Waisman Center, Department of Comparative Biosciences, and School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Nat Commun. 2015 Nov 26;6:8966. doi: 10.1038/ncomms9966.
Glia play critical roles in maintaining the structure and function of the nervous system; however, the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined. Here we use Alexander disease, a serious degenerative neurological disorder caused by astrocyte dysfunction, to identify glial-derived NO as a signalling molecule triggering astrocyte-mediated neuronal degeneration. We further find that NO acts through cGMP signalling in neurons to promote cell death. Glial cells themselves also degenerate, via the DNA damage response and p53. Our findings thus define a specific mechanism for glial-induced non-cell autonomous neuronal cell death, and identify a potential therapeutic target for reducing cellular toxicity in Alexander disease, and possibly other neurodegenerative disorders with glial dysfunction.
神经胶质细胞在维持神经系统的结构和功能方面发挥着关键作用；然而，在人类疾病状态下，星形胶质细胞对神经退行性变的具体贡献仍 largely 未明确。在这里，我们利用亚历山大病（一种由星形胶质细胞功能障碍引起的严重退行性神经疾病）来确定神经胶质细胞衍生的一氧化氮作为触发星形胶质细胞介导的神经元变性的信号分子。我们进一步发现，一氧化氮通过神经元中的 cGMP 信号传导促进细胞死亡。神经胶质细胞自身也会通过 DNA 损伤反应和 p53 发生变性。因此，我们的研究结果确定了一种神经胶质细胞诱导的非细胞自主性神经元细胞死亡的特定机制，并确定了一个潜在的治疗靶点，以降低亚历山大病以及可能其他伴有神经胶质细胞功能障碍的神经退行性疾病中的细胞毒性。
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