Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis.
Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis.
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DOI：
10.1242/dmm.010710
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发表时间：
2013-05
影响因子：
4.3
通讯作者：
Zarnescu DC
中科院分区：
文献类型：
--
作者：
Estes PS;Daniel SG;McCallum AP;Boehringer AV;Sukhina AS;Zwick RA;Zarnescu DC
肌萎缩侧索硬化症（ALS）是一种以复杂的神经元和神经胶质表型为特征的致死性疾病。最近，基于RNA的机制已经通过RNA结合蛋白（如TDP-43）与ALS联系起来，已经使用从酵母到啮齿动物的模型在体内研究了TDP-43。我们已经开发了基于TDP-43的ALS果蝇模型，其概括了病理学的几个方面，包括运动神经元损失、运动功能障碍和存活率降低。在这里，我们报告了在神经元和神经胶质细胞中表达野生型和四种不同ALS相关TDP-43突变的表型后果。我们发现TDP-43驱动的神经变性表型是剂量和年龄依赖性的。在运动神经元中，TDP-43似乎仅限于细胞核，由于突变体而非野生型蛋白表达，细胞核显著畸形。在神经胶质和发育中的神经上皮中，TDP-43与细胞质点相关。含TDP-43的RNA颗粒在培养的运动神经元中是能动的，尽管野生型和突变体变体表现出不同的动力学特性。在神经肌肉接头处，TDP-43在运动神经元与神经胶质中的表达导致看似相反的突触表型，令人惊讶的是，这转化为相当的运动缺陷。最后，我们探索睡眠作为TDP-43表达的行为读数，并发现与过度兴奋一致的睡眠片段化证据，这是ALS的一种建议机制。这些发现支持了这样的观点，即虽然运动神经元和神经胶质都参与ALS病理学，但在细胞水平上，它们对TDP-43表现出不同的反应。此外，我们的数据表明，个别TDP-43等位基因利用不同的分子机制，这将是重要的开发治疗策略。
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by complex neuronal and glial phenotypes. Recently, RNA-based mechanisms have been linked to ALS via RNA-binding proteins such as TDP-43, which has been studied in vivo using models ranging from yeast to rodents. We have developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of pathology, including motor neuron loss, locomotor dysfunction and reduced survival. Here we report the phenotypic consequences of expressing wild-type and four different ALS-linked TDP-43 mutations in neurons and glia. We show that TDP-43-driven neurodegeneration phenotypes are dose- and age-dependent. In motor neurons, TDP-43 appears restricted to nuclei, which are significantly misshapen due to mutant but not wild-type protein expression. In glia and in the developing neuroepithelium, TDP-43 associates with cytoplasmic puncta. TDP-43-containing RNA granules are motile in cultured motor neurons, although wild-type and mutant variants exhibit different kinetic properties. At the neuromuscular junction, the expression of TDP-43 in motor neurons versus glia leads to seemingly opposite synaptic phenotypes that, surprisingly, translate into comparable locomotor defects. Finally, we explore sleep as a behavioral readout of TDP-43 expression and find evidence of sleep fragmentation consistent with hyperexcitability, a suggested mechanism in ALS. These findings support the notion that although motor neurons and glia are both involved in ALS pathology, at the cellular level they can exhibit different responses to TDP-43. In addition, our data suggest that individual TDP-43 alleles utilize distinct molecular mechanisms, which will be important for developing therapeutic strategies.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.1
作者：
Gustafson, K;Boulianne, GL
通讯作者：
Boulianne, GL
影响因子：
5.3
作者：
Bronk, P;Nie, ZP;Zinsmaier, KE
通讯作者：
Zinsmaier, KE
影响因子：
3.5
作者：
Fallini, Claudia;Bassell, Gary J.;Rossoll, Wilfried
通讯作者：
Rossoll, Wilfried