Analysis of brain infiltrating monocyteic cell in lysosomal disease

GM2神经节苷脂沉积症是一种溶酶体β-己糖胺酶(Hex)缺乏症，涉及包括GM2神经节苷脂(GM2)在内的未降解底物的过度积聚和进行性神经变性。在本研究中，我们从Sandhoff病模型小鼠的骨髓中分离出单核细胞系，并证明了单核细胞系中信号转导的异常。我们发现，与野生型(WT)小鼠分离的细胞相比，SD单核细胞(MSD)MIP-1α的细胞偏头痛显著不同。此外，我们还观察到MSD细胞中cofilin磷酸化水平的增加。此外，MSD组PI3K活性是WT组的5倍左右。这些结果表明，MSD的PI3K上调依赖于包括GM2在内的自然底物的积累。这些发现可能代表了在GM2神经节苷脂沉着症中观察到的将浸润性细胞连接到脑内的机制。

GM2 gangliosidosis is a lysosomal beta-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside (GM2), and progressive neurodegeneration. In this study, we isolated monocyte cell line from the bone marrow of Sandhoff disease model mice, and demonstrated the abnormalities of signal transduction in monocyte cell lines. We found remarkable differences in the cell migraion for MIP-1alpha of SD monocyte (MSD) when compared to cells isolated from wild type (WT) mice, with activation of MSD. In addition, we observed increased Cofilin phosphorylation in MSD cells. Moreover, PI3K activity was increased about 5times in MSD compare with that of WT. These results suggest that the up-regulation of PI3K of MSD was dependent upon accumulation of natural substrates, including GM2. These findings may represent a mechanism in linking infiltrating cells into brain observed in GM2 gangliosidosis.