Neuroscience Laboratory and Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
J Neuropathol Exp Neurol. 2010 Sep;69(9):945-58. doi: 10.1097/NEN.0b013e3181efa658.
The X-linked demyelinating/type I Charcot-Marie-Tooth neuropathy (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32. Connexin32 is expressed by myelinating Schwann cells and forms gap junctions in noncompact myelin areas, but axonal involvement is more prominent in X-linked compared with other forms of demyelinating Charcot-Marie-Tooth disease. To clarify the cellular and molecular mechanisms of axonal pathology in CMT1X, we studied Gjb1-null mice at early stages (i.e. 2-4 months old) of the neuropathy, when there is minimal or no demyelination. The diameters of large myelinated axons were progressively reduced in Gjb1-null mice compared with those in wild-type littermates. Furthermore, neurofilaments were relatively more dephosphorylated and more densely packed starting at 2 months of age. Increased expression of β-amyloid precursor protein, a marker of axonal damage, was also detected in Gjb1-null nerves. Finally, fast axonal transport, assayed by sciatic nerve ligation experiments, was slower in distal axons of Gjb1-null versus wild-type animals with reduced accumulation of synaptic vesicle-associated proteins. These findings demonstrate that axonal abnormalities including impaired cytoskeletal organization and defects in axonal transport precede demyelination in this mouse model of CMT1X.
X 连锁脱髓鞘/Ⅰ型腓骨肌萎缩症（CMT1X）是一种遗传性周围神经病，由编码间隙连接蛋白连接蛋白 32 的 GJB1 基因突变引起。连接蛋白 32 由髓鞘施万细胞表达，并在非致密髓鞘区形成间隙连接，但与其他脱髓鞘腓骨肌萎缩症形式相比，X 连锁型更突出轴突受累。为了阐明 CMT1X 轴突病理学的细胞和分子机制，我们在神经病的早期（即 2-4 月龄）研究了 Gjb1 基因敲除小鼠，此时脱髓鞘程度最小或没有。与野生型同窝仔相比，Gjb1 基因敲除小鼠的大髓鞘轴突直径逐渐减小。从 2 月龄开始，神经丝的去磷酸化程度相对更高，排列更紧密。还检测到 Gjb1 基因敲除神经中β淀粉样前体蛋白表达增加，这是轴突损伤的标志物。最后，通过坐骨神经结扎实验检测到快速轴突运输，与野生型动物相比，Gjb1 基因敲除动物的远端轴突运输速度较慢，突触小泡相关蛋白的积累减少。这些发现表明，在这种 CMT1X 小鼠模型中，轴突异常包括细胞骨架组织受损和轴突运输缺陷，先于脱髓鞘发生。
