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However, the possibility also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron\u2010glia coculture system, we found that wild\u2010type neurons cultured on a layer of NPC1\u2212\/\u2212 astrocytes showed decreased neurite growth compared with those cultured on wild\u2010type astrocytes. RT\u2010PCR and immunohistochemical assessments showed significantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC1\u2212\/\u2212 astrocyte cultures than in wild\u2010type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC1\u2212\/\u2212 mice. Administration of 17\u03b2\u2010estradiol to neonatal NPC1\u2212\/\u2212 mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals' life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.20563","type":"journal-article","created":{"date-parts":[[2007,8,17]],"date-time":"2007-08-17T16:22:12Z","timestamp":1187367732000},"page":"1509-1518","source":"Crossref","is-referenced-by-count":66,"title":["Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann\u2010Pick disease type C"],"prefix":"10.1002","volume":"55","author":[{"given":"Gang","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai\u2010Min","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Ren","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Song","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shumin","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2007,8,17]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-1363"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00345-5"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20868"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.228"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.142.8.3302"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.020"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1086071"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1750"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.09.065"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00568.2004"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0081-05.2005"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20404"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-12-04897.2002"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00517-6"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.1149"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00230-5"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2003-0323"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(92)90236-O"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1073"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313828200"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/35058528"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.06.017"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/00034983.1990.11812449"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.03733.x"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20041694"},{"key":"e_1_2_6_27_1","first-page":"1","article-title":"Endocrine disrupters as disrupters of brain function: a neurosteroid viewpoint","volume":"11","author":"Kawato S","year":"2004","journal-title":"Environ Sci"},{"key":"e_1_2_6_28_1","doi-asserted-by":"crossref","first-page":"10613","DOI":"10.1523\/JNEUROSCI.22-24-10613.2002","article-title":"An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain","author":"King SR","year":"2002","journal-title":"J Neurosci"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0010081"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0815fje"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00422-6"},{"key":"e_1_2_6_32_1","doi-asserted-by":"crossref","first-page":"9181","DOI":"10.1016\/S0021-9258(18)48065-9","article-title":"Cholesterol sulfate inhibits adrenal mitochondrial cholesterol side chain cleavage at a site distinct from cytochrome P\u2010450scc. 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