C1型尼曼-匹克氏症小鼠嗅球细胞的病理变化

闫欣; 乔梁; 林俊堂

解剖学报 ›› 2016, Vol. 47 ›› Issue (1) : 2-6.

神经生物学

C1型尼曼-匹克氏症小鼠嗅球细胞的病理变化

闫欣¹,乔梁¹,林俊堂²

作者信息 +

The pathological changes of the olfactory bulbs in the Niemann-pick type C1 mice

Xin YAN¹,Liang QIAOLin Juntang

Author information +

文章历史 +

摘要

目的通过观察NPC1基因突变型小鼠嗅球的形态学变化，探讨C1型尼曼-匹克氏症对嗅觉系统的影响。方法提取小鼠尾部组织DNA进行聚合酶链式反应（PCR）检测种系基因型；选取出生后第30 d的野生型和突变型小鼠，采用免疫组织化学方法观察对比嗅球系统中神经元轴突的形态结构和髓鞘形成，以及SMI31和MBP的表达情况；TUNEL方法染色检测嗅球神经细胞的凋亡情况。结果 NPC1基因突变型小鼠嗅球中NPC1蛋白表达明显降低，神经细胞凋亡增加；SMI31免疫荧光显示嗅球内神经丝蛋白发生变性聚集，导致神经纤维缠结；同时，MBP蛋白表达量明显降低，髓鞘形成受到抑制。结论 NPC1基因突变能够引起嗅球神经细胞发生病理性变化，影响嗅觉系统的正常功能。

Abstract

Objective To examine the impact of Niemann-pick type C1 disease on the olfactory system, we investigated the morphological changes of the olfactory bulbs in NPC1 mutant mouse. Methods The genomic DNA was extracted from mice tails for genotyping by PCR；30-day-old mice including wild type and NPC1 gene mutation were selected, and immunohistochemistry was performed to examine and compare the axonal structure, the myelination process, as well as the expression of SMI31 and MBP in the olfactory bulbs；The cell apoptosis were analyzed by TUNEL assay. Results In NPC1-/- mice, the expression of NPC1 protein is rarely detected, but TUNEL-positive cells are increased. Immunofluorescence using SMI31 antibody indicates accumulation of neurofilament and formation of axonal spheroids in the NPC1-/- olfactory bulbs. Furthermore, the decreased expression of MBP protein is also found in NPC1-/- olfactory system, which is associated with perturbed myelination. Conclusion Our data show pathological changes in the olfactory bulbs of NPC1 mutant mice, which is accompanied by olfactory defects.

导出引用

闫欣乔梁林俊堂. C1型尼曼-匹克氏症小鼠嗅球细胞的病理变化[J]. 解剖学报. 2016, 47(1): 2-6

Xin YAN Liang QIAO Lin Juntang. The pathological changes of the olfactory bulbs in the Niemann-pick type C1 mice[J]. Acta Anatomica Sinica. 2016, 47(1): 2-6

参考文献

[1] Ninomiya H.Intracellular cholesterol transport by NPC1/NPC2: Mysteries of Niemann-Pick disease type C[J].Functional and Structural Biology on the Lipo-network, 2006, :1-15 [2]Maulik M, Thinakaran G, Kar S.Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking niemann-pick type C1 protein[J].PLoS One, 2013, 8(1):e54605- [3]Vance J E.Transfer of cholesterol by the NPC team[J].Cell Metabolism, 2010, 12(2):105-106 [4]Bu B, Li J, Davies P, et al.Deregulation of cdk5,hyperphosphorylation,and cytoskeletal pathology in the Niemann-Pick type C murine model[J].The Journal of Neuroscience, 2002, 22(15):6515-6525 [5]Patterson M C, Hendriksz C J, Walterfang M, et al.Recommendations for the diagnosis and management of Niemann–Pick disease type C: an update[J].Molecular genetics and metabolism, 2012, 106(3):330-344 [6] Pressey S N, Smith D A, Wong A M, et al.Early glial activation,synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice[J].Neurobiology of Disease, 2012, 45(3):1086-1100 [7]Yan X, Yang F, Lukas J, et al.Hyperactive glial cells contribute to axonal pathologies in the spinal cord of Npc1 mutant mice[J].Glia, 2014, 62(7):1024-1040 [8]Attems J, Jellinger K A.Olfactory tau pathology in Alzheimer disease and mild cognitive impairment[J].Clinical Neuropathology, 2006, 25(6):265-271 [9]Saunders-Pullman R, Hagenah J, Dhawan V, et al.Gaucher disease ascertained through a Parkinson’s center: imaging andclinical characterization[J].Movement Disorders, 2010, 25(10):1364-1372 [10]Loftus S K, Morris J A, Carstea E D, et al.Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene[J].Science, 1997, 277(5323):232-235 [11] Djordjevic J, Jones-Gotman M, De Sousa K, et al.Olfaction in patients with mild cognitive impairment and Alzheimer's disease[J].Neurobiology of Aging, 2008, 29(5):693-706 [12]McNeill A, Duran R, Proukakis C, et al.Hyposmia and cognitive impairment in Gaucher disease patients and carriers[J].Movement Disorders, 2012, 27(4):526-532 [13]Liao G, Yao Y, Liu J, et al.Cholesterol accumulation isassociated with lysosomal dysfunction and autophagic stress in Npc1-- mouse brain[J].The American Journal of Pathology, 2007, 171(3):962-975 [14]Sarna J R, Larouche M, Marzban H, et al.Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease[J].The Journal of Comparative Neurology, 2003, 456(3):279-291 [15]Bi X, Liao G.Autophagic-lysosomal dysfunction and neurodegeneration in Niemann-Pick Type C mice: lipid starvation or indigestion[J].Autophagy, 2007, 3(6):646-648 [16]Kodam A, Maulik M, Peake K, et al.Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains[J].Glia, 2010, 58(11):1267-1281 [17]Yan X, Lukas J, Witt M, et al.Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse[J].Metabolic Brain Disease, 2011, 26(4):299-306 [18]Takikita S, Fukuda T, Mohri I, et al.Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse[J].Journal of Neuropathology and Experimental Neurology, 2004, 63(6):660-673 [19]Wang P Y, Weng J, Anderson R G.OSBP is a cholesterol-regulated scaffolding protein in control of ERK 12 activation[J].Science, 2005, 307(5714):1472-1476 [20]Fünfschilling U, Jockusch WJ, Sivakumar N, et al.Critical time window of neuronal cholesterol synthesis during neurite outgrowth[J].The Journal of Neuroscience, 2012, 32(22):7632-7645 [21]Hallows J L, Iosif R E, Biasell R D, et al.p35p25 is not essential for tau and cytoskeletal pathology or neuronal loss in Niemann-Pick type C disease[J].The Journal of Neuroscience, 2006, 26(10):2738-2744 [22]Cotter L, Oz?elik M, Jacob C, et al.Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination[J].Science, 2010, 328(5984):1415-1418 [23]Lee Y, Morrison B M, Li Y, et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration[J].Nature, 2012, 487(7408):443-448