Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
复制标题
DOI：
10.1016/j.nbd.2014.09.012
复制
发表时间：
2015-01
影响因子：
6.1
通讯作者：
Brundin, Patrik
中科院分区：
文献类型：
--
作者：
Nordstrom, Ulrika;Beauvais, Genevieve;Ghosh, Anamitra;Sasidharan, Baby Chakrapani Pulikkaparambil;Lundblad, Martin;Fuchs, Julia;Joshi, Rajiv L.;Lipton, Jack W.;Roholt, Andrew;Medicetty, Satish;Feinstein, Timothy N.;Steiner, Jennifer A.;Galvis, Martha L. Escobar;Prochiantz, Alain;Brundin, Patrik
关键词：
目前对帕金森病（PD）发病机制的研究需要相关的动物模型，模拟神经元功能障碍和变性的逐渐和进行性发展，疾病的特点。enrailed 1（En 1）是一种同源框转录因子，对中脑多巴胺能神经元的发育和存活至关重要，其多态性与散发性PD相关。这表明En 1突变小鼠可能是一种有希望的候选PD模型。事实上，缺乏一个En 1等位基因的小鼠在成年期表现出线粒体复合物I活性降低和进行性中脑多巴胺神经元变性，这两个特征都与PD相关。我们的目的是进一步表征这些En 1 +/-小鼠的疾病样表型，重点是早期神经退行性变化，可用于对未来疾病改善研究的疗效进行评分。我们在En 1 +/-小鼠中观察到多巴胺能黑质纹状体通路的早期终末缺陷。在黑质（SN）中多巴胺能神经元的显著损失之前几周，我们发现表达高水平多巴胺能神经元标记物TH、VMAT 2和DAT的纹状体末梢营养不良和肿胀。利用透射电子显微镜，我们确定了电子致密体符合异常自噬空泡在这些终端sesophageal。与这些发现一致，我们检测到在En 1 +/-小鼠的腹侧中脑和黑质多巴胺能神经元中mTOR通路的上调，同时自噬标记物LC 3B的下调。这支持了自噬蛋白降解在一个En 1等位基因缺失的情况下减少的观点。我们成像的黑质纹状体通路使用的EQUITY技术，并观察到许多破碎的轴突在内侧前脑束的En 1 +/ -小鼠，与轴突维护失败。使用在体电化学，我们发现，在背侧纹状体的黑质纹状体终端多巴胺的释放和再摄取严重不足。我们的研究结果支持En 1 +/-黑质纹状体神经元的进行性退行性变性，类似于PD中发生的情况。我们建议使用En 1 +/-小鼠作为模型将为PD发病机制提供进一步的关键见解，并提出轴突末端完整性和功能可用于估计多巴胺能神经元的健康和实验性PD疗法的功效。
Current research on Parkinson’s disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1+/– mice with focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1+/– mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra (SN) could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of En1+/– mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of En1+/ – mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1+/– nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using En1+/– mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
登录
查看更多内容
影响因子：
8.6
作者：
Bezard, Erwan;Yue, Zhenyu;Kirik, Deniz;Spillantini, Maria Grazia
通讯作者：
Spillantini, Maria Grazia
影响因子：
17.1
作者：
Decressac, Mickael;Kadkhodaei, Banafsheh;Bjorklund, Anders
通讯作者：
Bjorklund, Anders
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1155/2012/429524
发表时间：
2012
期刊：
Parkinson's disease
影响因子：
--
作者：
Sánchez-Pérez AM;Claramonte-Clausell B;Sánchez-Andrés JV;Herrero MT
通讯作者：
Herrero MT
影响因子：
30.8
作者：
Le, WD;Xu, PY;Vassilatis, DK
通讯作者：
Vassilatis, DK