Gazi Michal, Shyamala Baragur V, Bhat Krishna Moorthi
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Dev Biol. 2009 Oct 1;334(1):311-23. doi: 10.1016/j.ydbio.2009.07.024. Epub 2009 Jul 25.
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.
肿瘤抑制形态发生素帕奇（Patched，Ptc）与尼曼-匹克C1（NPC1）蛋白具有广泛的同源性。NPC病是一种儿科进行性致命神经退行性疾病，被认为是由于神经元中胆固醇异常蓄积所致。在此，我们报告Ptc突变的成年果蝇会发生进行性神经退行性疾病，其大脑中含有膜性和层状内含物。突变成年果蝇大脑中的突触终末数量也显著减少。有趣的是，给野生型果蝇喂食胆固醇会在其大脑中产生内含物，但不会引发疾病。然而，给突变果蝇喂食胆固醇会增加突触连接并抑制疾病。我们的结果表明，突变大脑中以膜性物质和内含物形式存在的胆固醇隔离会影响细胞功能可利用的胆固醇库。这进而对突触数量产生负面影响并导致疾病状态。与此一致的是，在Ptc突变体中胆固醇酯库减少，而胆固醇介导的疾病抑制伴随着胆固醇酯增加。我们进一步表明，Ptc在此过程中并非直接发挥作用，因为刺猬蛋白（Hedgehog）功能获得也会诱导相同疾病，同时胆固醇酯水平降低。我们认为，Ptc功能丧失通过两种不同方式导致神经退行性变：解除对干扰脂质转运基因的抑制，以及解除对脂质转运之外基因的抑制；这两类基因的功能最终都汇聚于突触连接。
