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In this study, we demonstrate that inhibition of intracellular cholesterol trafficking in primary neurons by class\u20032 amphiphiles, which mimics the major biochemical and cellular feature of NPC1, led to not only impaired mitochondrial function but also activation of the mitochondrial apoptosis pathway. In activation of this pathway both cytochrome\u2003<jats:italic>c<\/jats:italic> and Smac\/Diablo were released but apoptosis\u2010inducing factor (AIF) was not involved. Treatment of the neurons with taurine, a caspase\u20039\u2010specific inhibitor, could prevent the amphiphile\u2010induced apoptotic cell death, suggesting that formation of apoptosome, followed by caspase\u20039 and caspase\u20033 activation, might play a critical role in the neuronal death pathway. Taken together, the mitochondria\u2010dependent death cascade induced by blocking intracellular cholesterol trafficking was caspase dependent. The findings provide clues for both understanding the molecular basis of neurodegeneration in NPC1 disease and developing therapeutic strategies for treatment of this disorder.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03733.x","type":"journal-article","created":{"date-parts":[[2006,3,3]],"date-time":"2006-03-03T11:00:57Z","timestamp":1141383657000},"page":"280-291","source":"Crossref","is-referenced-by-count":29,"title":["Neuronal cell death caused by inhibition of intracellular cholesterol trafficking is caspase dependent and associated with activation of the mitochondrial apoptosis pathway"],"prefix":"10.1111","volume":"97","author":[{"given":"Zhili","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsong","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam Sang","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu\u2010Tian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,3,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00381-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200207071"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg423"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401240"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-13-05645.2003"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)35908-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9084(02)01376-7"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4261-04.2005"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(98)00123-3"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.01.066"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200202130"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207517"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.14.5.729"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(86)90368-6"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00008-8"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.68.1.383"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(89)90397-9"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-5846(03)00021-6"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404990102"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01220.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205406200"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007519419342"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.3.601"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/10084"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/74994"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2003.10.004"},{"key":"e_1_2_7_28_1","doi-asserted-by":"crossref","first-page":"29\u2003371","DOI":"10.1016\/S0021-9258(18)43886-0","article-title":"Cholesterol homeostasis. 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