Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models
Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models
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DOI：
10.1093/hmg/ddt528
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发表时间：
2014-03-15
影响因子：
3.5
通讯作者：
Manfredi, Giovanni
中科院分区：
文献类型：
--
作者：
Magrane, Jordi;Cortez, Czrina;Manfredi, Giovanni
神经元线粒体形态异常发生在与SOD 1和TDP 43突变相关的家族性肌萎缩侧索硬化症（ALS）模型中。这些异常与线粒体轴突运输缺陷有关，但这两种不同遗传形式的ALS中线粒体形态和运输改变之间的时空关系尚未在体内研究。为了解决这个问题，我们将SOD1（野生型SOD1（WT）和突变型SOD1（G93A））或TDP43（突变型TDP43（A315T））转基因小鼠与表达靶向神经元线粒体的荧光蛋白Dendra（mitoDendra）的小鼠杂交。在疾病过程中的不同时间点，我们研究了活小鼠完整坐骨神经中的线粒体转运，并分析了从脊髓到运动末梢的多个部位的轴突线粒体形态。在45日龄时，在症状发作之前，在SOD1（G93A）和TDP43（A315T）小鼠中检测到逆行线粒体转运缺陷，但在SOD1（WT）中未检测到。在疾病后期，两种突变小鼠系的线粒体顺行运输也受到影响。在SOD1（G93A）小鼠中，15日龄时肾脏形态学异常明显，因此先于转运异常。相反，在TDP43（A315T）小鼠中，运输缺陷发作后出现形态异常。总之，这些发现表明，神经元线粒体运输和形态异常发生在体内，它们是不同遗传形式的ALS的常见致病因素。与此同时，两种家族性ALS小鼠模型之间线粒体异常的时空表现差异意味着可能涉及不同的分子机制。
Neuronal mitochondrial morphology abnormalities occur in models of familial amyotrophic lateral sclerosis (ALS) associated with SOD1 and TDP43 mutations. These abnormalities have been linked to mitochondrial axonal transport defects, but the temporal and spatial relationship between mitochondrial morphology and transport alterations in these two distinct genetic forms of ALS has not been investigated in vivo. To address this question, we crossed SOD1 (wild-type SOD1(WT) and mutant SOD1(G93A)) or TDP43 (mutant TDP43(A315T)) transgenic mice with mice expressing the fluorescent protein Dendra targeted to mitochondria in neurons (mitoDendra). At different time points during the disease course, we studied mitochondrial transport in the intact sciatic nerve of living mice and analyzed axonal mitochondrial morphology at multiple sites, spanning from the spinal cord to the motor terminals. Defects of retrograde mitochondrial transport were detected at 45 daysof age, before the onset of symptoms, in SOD1(G93A) and TDP43(A315T) mice, but not in SOD1(WT). At later disease stages, also anterograde mitochondrial transport was affected in both mutant mouse lines. In SOD1(G93A) mice, mitochondrialmorphological abnormalities were apparent at 15 days of age, thus preceding transport abnormalities. Conversely, in TDP43(A315T) mice, morphological abnormalities appeared after the onset of transport defects. Taken together, these findings demonstrate that neuronal mitochondrial transport and morphology abnormalities occur in vivo and that they are common denominators of different genetic forms of the ALS. At the same time, differences in the temporal and spatial manifestation of mitochondrial abnormalities between the two mouse models of familial ALS imply that different molecular mechanisms may be involved.