Villani Guglielmo R D, Di Domenico Carmela, Musella Annapaola, Cecere Francesca, Di Napoli Daniele, Di Natale Paola
Department of Biochemistry and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.
Brain Res. 2009 Jul 7;1279:99-108. doi: 10.1016/j.brainres.2009.03.071. Epub 2009 May 3.
Sanfilippo B syndrome (Mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease due to mutations in the gene encoding alpha-N-acetylglucosaminidase and is characterized by a severe neurological disorder. Although several studies have been reported for the murine model of the disease, the molecular basis and the sequence of events leading to neurodegeneration remain to be clarified. We previously suggested the possible involvement of the reactive oxygen species in the disease pathogenesis. In the present paper we extended the analysis of oxidative stress by evaluating the production of superoxide ions throughout the CNS and by evaluating the effect of the stress on the cellular macromolecules. These approaches applied to one-month-old, three-month-old and six-month-old mice revealed that oxidative stress is present in the affected cerebrum and cerebellum tissues from one month from birth, and that it results primarily in protein oxidation, both in the cerebrum and cerebellum, with lipid peroxidation, and especially DNA oxidation, appearing milder and restricted essentially to the cerebellum. We also identified additional genes possibly associated with the neuropathology of MPS IIIB disease. Real time RT-PCR analysis revealed an altered expression of the Sod1, Ret, Bmp4, Tgfb, Gzmb and Prf1 genes. Since Gzmb and Prf1 are proteins secreted by NK/cytotoxic T-cells, these data suggest the involvement of cytotoxic cells in the neuronal pathogenesis. Extending our previous study, findings reported in the present paper show that oxidative stress and all the analyzed stress-related pathological changes occur very early in the disease course, most likely before one month of age.
桑菲利波B综合征（黏多糖贮积症IIIB型，MPS IIIB）是一种溶酶体贮积病，由编码α-N-乙酰氨基葡萄糖苷酶的基因突变引起，其特征为严重的神经紊乱。尽管已有多项关于该疾病小鼠模型的研究报道，但导致神经退行性变的分子基础和事件序列仍有待阐明。我们之前曾提出活性氧可能参与该疾病的发病机制。在本文中，我们通过评估整个中枢神经系统中超氧阴离子的产生以及应激对细胞大分子的影响，扩展了对氧化应激的分析。应用于1月龄、3月龄和6月龄小鼠的这些方法显示，氧化应激在出生后1个月起就存在于受影响的大脑和小脑组织中，并且主要导致大脑和小脑中的蛋白质氧化，脂质过氧化尤其是DNA氧化则较轻，且基本上局限于小脑。我们还鉴定了其他可能与MPS IIIB疾病神经病理学相关的基因。实时逆转录聚合酶链反应分析显示Sod1、Ret、Bmp4、Tgfb、Gzmb和Prf1基因的表达发生了改变。由于Gzmb和Prf1是自然杀伤细胞/细胞毒性T细胞分泌的蛋白质，这些数据表明细胞毒性细胞参与了神经元发病机制。扩展我们之前的研究，本文报道的结果表明氧化应激以及所有分析的与应激相关的病理变化在疾病进程中很早就出现了，很可能在1月龄之前。
