Multiple approaches of the therapy for lysosomal diseases affected with central nervous system

溶酶体疾病是由未消化的底物在溶酶体内积累引起的。影响中枢神经系统的溶酶体疾病由于重组酶不能通过血脑屏障进入而难以治疗。我们尝试了几个项目来接近这些疾病的治疗方法，如下；1)表达影响酶：我们试图构建正常半乳糖脑苷酶在酵母中大规模表达，但表达率不够好。2)抑制鞘脂合成酶：我们发现环丝氨酸可以抑制精神素的产生。我们将检查环丝氨酸作用的剂量依赖性。3)分子修饰子：皂苷A被证实是半乳糖脑苷酶的激活剂，可能是半乳糖脑苷酶的修饰子。我们成功地在酵母表达系统中表达皂苷A。纯化的皂苷A能够激活β-葡萄糖苷酶和半乳糖脑苷酶。4)活化受影响的酶：产生的皂苷A可能与酶结合并使其稳定。我们正在体内分析这种效应。5)阻断细胞凋亡级联：检测TDAG8的表达谱，分析抗TDAG8抗体的作用。

Lysosomal diseases were caused by the accumulation of undigested substrates within lysosome. The lysosomal diseases affected in the central nervous system were hard to treat because the recombinant enzyme could not be entered through blood brain barrier. We tried several projects to approach the therapy of these disease, as follows ;1)Express affected enzyme: We tried to construct for the normal galactocerebrosidase to express in large-scale in yeast, however the ratio of expression was not good enough.2)Inhibition of synthetic enzyme of sphingolipid : We realize that cycloserine was confirmed to inhibit production of psychosine. We will check dose dependency for the effect of cycloserine.3)Molecular shaperon : Saposine A was proven to be the activator of galactocerebrosidase and might be shaperon for it. We were succeeded in express saposin A in yeast expression system. Purified saposin A was able to activate β-glucosidase and galactocerebrosidase.4)Activation of affected enzyme: The produced saposin A might be able to bind enzyme and stabilyze them. We are analyzing this effect in vivo.5)Block apoptosis cascade : We check the expression profile of TDAG8 and analyzed the effect of antibody against TDAG8.