FELINE NIEMANN - PICK TYPE C

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在NCRR P40补助金的支持下，将唯一一个患有C型尼曼匹克病（NPC）的猫群从科罗拉多州立大学转移到宾夕法尼亚大学兽医学院。NPC基因中的点突变是导致猫的临床症状的原因。跨膜NPC 1蛋白的遗传缺陷导致神经内脏胆固醇鞘糖脂病，其特征在于除了癫痫发作和肝脾肿大之外，还存在严重的进行性认知和运动缺陷。这种疾病的代谢基础尚未完全了解，但NPC 1蛋白的缺乏导致内吞胆固醇的异常细胞内转运，以及由于未酯化胆固醇和鞘糖脂（乳糖神经酰胺、葡萄糖神经酰胺和神经节苷脂）在溶酶体和晚期内体中的储存而导致的细胞肿胀。神经节苷脂在神经元中的储存，特别是GM 2神经节苷脂，导致皮质锥体神经元和屏状核和杏仁核的多极细胞上的巨神经元形成和异位树突发生。脑的神经病理学还包括浦肯野细胞死亡、GABA能神经元的轴突球体形成、脱髓鞘和由tau蛋白组成的神经元缠结。在NPC猫中进行的研究对于确定GABA能神经元中轴突球体的形成以及神经轴突营养不良与神经功能障碍的相关性至关重要。NPC疾病的猫模型也用于鉴定GM 2和GM 3神经节苷脂和未酯化胆固醇的晚期内体/溶酶体积累以及GM 2储存与巨核形成和异常树突发生的关联。为了检查鞘糖脂储存对NPC疾病的影响，三只NPC猫先前用N-丁基脱氧野尻霉素（NB-DNJ）治疗，NB-DNJ是一种所有基于葡萄糖神经酰胺的鞘糖脂（包括乳糖神经酰胺和神经节苷脂）的抑制剂。每天用NB-DNJ治疗23至54天的NPC猫显示意向性震颤和共济失调的发作延迟，小清蛋白阳性轴突球体减少，钙结合蛋白阳性浦肯野细胞数量增加，脑神经节苷脂积累减少，寿命延长。这项研究强调了鞘糖脂储存对疾病进展的重要性，并且是第一种有效改善任何NPC疾病物种疾病进展的疗法。 正在进行研究，以进一步确定神经系统疾病的进展，在猫模型NPC疾病使用神经系统检查，电诊断测试，核磁共振成像（NMR），生物化学和组织病理学。与这些研究同时，我们正在评估N-丁基脱氧野尻霉素、神经类固醇别孕烯醇酮以及别孕烯醇酮和N-丁基脱氧野尻霉素联合治疗猫NPC神经系统疾病的疗效。我们假设，用这些药物治疗NPC猫将延迟神经功能障碍体征的发作，改善电诊断和NMR异常，延长寿命，增加浦肯野细胞存活率，并减少脑中神经节苷脂的储存。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The only colony of cats with Niemann-Pick type C disease (NPC) was moved to the School of Veterinary Medicine of the University of Pennsylvania from Colorado State University using support from the NCRR P40 grant. A point mutation in the NPC gene is responsible for clinical signs in cats. Genetic deficiency of the transmembrane NPC1 protein results in a neurovisceral cholesterol-glycosphingolipidosis, which is characterized by severe and progressive cognitive and motor deficits in addition to seizures and hepatosplenomegaly. The metabolic basis of this disease is not fully understood but deficiency in NPC1 protein results in the abnormal intracellular transport of endocytosed cholesterol, and in cellular swelling due to the storage of unesterified cholesterol and glycosphingolipids (lactosylceramide, glucosylceramide, and gangliosides) in lysosomes and late endosomes. The storage of gangliosides in neurons, specifically GM2 ganglioside, results in meganeurite formation and ectopic dendritogenesis on cortical pyramidal neurons and multipolar cells of the claustrum and amygdala. Neuropathology of the brain also includes Purkinje cell death, axonal spheroid formation of GABAergic neurons, demyelination, and neurofibrillary tangles composed of tau protein. Studies performed in the NPC cat were critical for identifying axonal spheroid formation in GABAergic neurons and the correlation of neuroaxonal dystrophy with neurological dysfunction. The feline model of NPC disease was also used to identify the late endosomal/lysosomal accumulation of GM2 and GM3 gangliosides and unesterified cholesterol as well as the association of GM2 storage with meganeurite formation and abnormal dendritogenesis. To examine the effect of glycosphingolipid storage on NPC disease, three NPC cats were previously treated with N-bultyldeoxynojirimycin (NB-DNJ), an inhibitor of all glucosylceramide-based glycosphinglipids including lactosylceramide and the gangliosides. NPC cats treated with NB-DNJ daily for 23 to 54 days showed a delay in the onset of intention tremor and ataxia, diminished Parvalbumin-positive axonal spheroids, increased numbers of Calbindin-positive Purkinje cells, a reduction in brain ganglioside accumulation, and an increase in life span. This study underscored the importance of glycosphingolipid storage on disease progression and was the first therapy to effectively ameliorate disease progression in any species with NPC disease. Studies are being performed to further define the progression of nervous system disease in the feline model NPC disease using neurological examination, electrodiagnostic testing, nuclear magnetic resonance imaging (NMR), biochemistry, and histopathology. Concurrent with these studies we are evaluating the efficacy of N-butyldeoxynojirimycin, the neurosteroid allopregnanolone, and the combination of allopregnanolone and N-butyldeoxynojirimycin, to treat nervous system disease in feline NPC. We hypothesize that the treatment of NPC cats with these drugs will delay the onset of signs of neurological dysfunction, improve electrodiagnostic and NMR abnormalities, increase lifespan, increase Purkinje cell survival, and decrease ganglioside storage in the brain.