A neurodegenerative disease affecting synaptic connections in Drosophila mutant for the tumor suppressor morphogen Patched.
A neurodegenerative disease affecting synaptic connections in Drosophila mutant for the tumor suppressor morphogen Patched.
复制标题
一种神经退行性疾病，影响果蝇突变体中肿瘤抑制因子形态发生素 Patched 的突触连接。
DOI：
10.1016/j.ydbio.2009.07.024
复制
发表时间：
2009
影响因子：
2.7
通讯作者：
Bhat,KrishnaMoorthi
中科院分区：
文献类型：
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作者：
Gazi,Michal;Shyamala,BaragurV;Bhat,KrishnaMoorthi
肿瘤抑制因子PATCHED(PTC)与Niemann-Pick-C1(NPC1)蛋白具有广泛的同源性。鼻咽癌是一种儿科、进行性和致命性神经退行性疾病，被认为是由于胆固醇在神经元中的异常积聚。在这里，我们报告，打补丁的突变成人发展为一种进行性神经退行性疾病，他们的大脑含有膜性和板层包裹体。此外，突变成人大脑中的突触终末数量也显著减少。有趣的是，给野生果蝇喂食胆固醇会在大脑中产生内涵体，但不会导致这种疾病。然而，给突变果蝇喂食胆固醇会增加突触连接并抑制这种疾病。我们的结果表明，在突变的大脑中以膜物质和包裹体的形式隔离胆固醇会影响细胞功能所需的胆固醇池。反过来，这对突触的数量产生了负面影响，并导致了疾病状态。与此一致的是，在PTC突变体中，胆固醇酯的库减少，胆固醇介导的疾病抑制伴随着胆固醇酯的增加。我们进一步证明，PTC在这一过程中并不直接起作用，因为对于Hedgehog来说，功能的获得也会导致同样的疾病，并降低胆固醇酯水平。我们认为，PTC功能的丧失通过两种不同的方式导致神经退化：抑制干扰脂质运输的基因，以及抑制脂质运输以外的基因；这两类基因的功能最终汇聚在突触连接上。
The tumor suppressor morphogen, Patched (Ptc), has an extensive homology to the Niemann–Pick-C 1 (NPC1) protein. The NPC disease is a paediatric, progressive and fatal neurodegenerative disorder thought to be due to an abnormal accumulation of cholesterol in neurons. Here, we report that patched mutant adults develop a progressive neurodegenerative disease and their brain contains membranous and lamellar inclusions. There is also a significant reduction in the number of synaptic terminals in the brain of the mutant adults. Interestingly, feeding cholesterol to wild type flies generates inclusions in the brain, but does not cause the disease. However, feeding cholesterol to mutant flies increases synaptic connections and suppresses the disease. Our results suggest that sequestration of cholesterol in the mutant brain in the form of membranous material and inclusions affects available pool of cholesterol for cellular functions. This, in turn, negatively affects the synaptic number and contributes to the disease-state. Consistent with this, in ptc mutants there is a reduction in the pool of cholesterol esters, and cholesterol-mediated suppression of the disease accompanies an increase in cholesterol esters. We further show that Ptc does not function directly in this process since gain of function for Hedgehog also induces the same disease with a reduction in the level of cholesterol esters. We believe that loss of function for ptc causes neurodegeneration via two distinct ways: de-repression of genes that interfere with lipid trafficking, and de-repression of genes outside of the lipid trafficking; the functions of both classes of genes ultimately converge on synaptic connections.