Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
School of Engineering and Applied Science, Harvard University, Cambridge, MA, 02138, USA.
Nat Commun. 2018 May 15;9(1):1899. doi: 10.1038/s41467-018-04269-7.
Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis.
神经胶质细胞越来越被认为是神经疾病发病机制中的积极参与者，但控制神经胶质功能和继发非细胞自主神经元损伤的关键途径和机制仍未完全定义。在这里，我们使用亚历山大病模型，这是一种由 GFAP 功能获得性突变引起的严重脑疾病，证明了 GFAP 的失调会导致机械敏感性信号级联的激活，其特征是 Hippo 途径的激活和随后 A 型层粘连蛋白的表达增加。重要的是，我们利用遗传学来验证失调的机械转导信号在促进行为异常和非细胞自主神经退行性变中的功能作用。此外，我们采用细胞生物学和生物物理学方法来表明，亚历山大病患者的脑组织硬度增加。我们的发现表明，改变的机械转导信号是驱动亚历山大病中神经元功能障碍和神经退行性变的关键病理级联，可能也与其他以神经胶质增生为特征的脑疾病有关。
