Mignot C, Boespflug-Tanguy O, Gelot A, Dautigny A, Pham-Dinh D, Rodriguez D
INSERM U546, Faculté de la Pitié Salpêtrière, 105 boulevard de l'hôpital, 75013 Paris, France.
Cell Mol Life Sci. 2004 Feb;61(3):369-85. doi: 10.1007/s00018-003-3143-3.
Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities. More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD. Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.
亚历山大病（AXD）是第一种原发性星形细胞疾病。这种脑病由胶质纤维酸性蛋白（GFAP）基因的显性突变引起，该基因编码星形胶质细胞的主要中间丝。在病理上，这种神经退行性疾病的特征是营养不良的星形胶质细胞含有与髓鞘异常相关的中间丝聚集体。已报道了20多种GFAP突变。其中许多聚集在几种中间丝之间的高度保守区域。与其他中间丝相关疾病相反，AXD似乎是聚集体诱导的功能毒性获得的结果。这得到了过表达人GFAP的小鼠的表型的支持。然而，GFAP基因敲除小鼠表现出AXD中存在的髓鞘异常和血脑屏障功能障碍。鉴于星形胶质细胞在脑生理学中的关键作用，星形胶质细胞功能失调并损害其他细胞功能的可能性有很多。本文在AXD的框架内讨论了生理病理假说。
