Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss.
Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss.
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DOI：
10.1016/j.pneurobio.2022.102297
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发表时间：
2022-08
影响因子：
6.7
通讯作者：
Li, Yun
中科院分区：
文献类型：
--
作者：
Liang, Bo;Thapa, Rashmi;Zhang, Gracie;Moffitt, Casey;Zhang, Yan;Zhang, Lifeng;Johnston, Amanda;Ruby, Hyrum P.;Barbera, Giovanni;Wong, Philip C.;Zhang, Zhaojie;Chen, Rong;Lin, Da-Ting;Li, Yun
关键词：
TAR DNA结合蛋白43 kDa（TARDBP或TDP-43）的错误定位是神经退行性疾病（如肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD））的主要病理标志。作为RNA结合蛋白，TDP-43在核区室中抑制非保守的隐蔽外显子以确保正常的转录组。来自动物模型和人类研究的多条证据支持这样的观点，即TDP-43的损失导致神经元损失，与其胞质聚集无关。然而，由功能丧失机制驱动的潜在致病途径仍然定义不清。我们采用遗传学方法来确定TDP-43损失对前额叶皮层（PFC）锥体神经元的影响。使用定制的微型成像系统，我们对自由行为的小鼠进行了长达7个月的重复体内钙成像。通过比较TDP-43耗尽和TDP-43完整小鼠之间PFC锥体神经元中的钙活性，我们证明了在短期TDP-43耗尽后表现出高活性钙活性的锥体神经元的数量显著增加，随后在神经元损失之前活性迅速下降。我们的研究结果表明，在ALS和FTD的早期阶段，由TDP-43缺失驱动的异常神经活动是致病途径。
Mislocalization of TAR DNA binding protein 43 kDa (TARDBP, or TDP-43) is a principal pathological hallmark identified in cases of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As an RNA binding protein, TDP-43 serves in the nuclear compartment to repress non-conserved cryptic exons to ensure the normal transcriptome. Multiple lines of evidence from animal models and human studies support the view that loss of TDP-43 leads to neuron loss, independent of its cytosolic aggregation. However, the underlying pathogenic pathways driven by the loss-of-function mechanism are still poorly defined. We employed a genetic approach to determine the impact of TDP-43 loss in pyramidal neurons of the prefrontal cortex (PFC). Using a custom-built miniscope imaging system, we performed repetitive in vivo calcium imaging from freely behaving mice for up to 7 months. By comparing calcium activity in PFC pyramidal neurons between TDP-43 depleted and TDP-43 intact mice, we demonstrated remarkably increased numbers of pyramidal neurons exhibiting hyperactive calcium activity after short-term TDP-43 depletion, followed by rapid activity declines prior to neuron loss. Our results suggest aberrant neural activity driven by loss of TDP-43 as the pathogenic pathway at early stage in ALS and FTD.
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DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
3
作者：
Liang B;Zhang L;Moffitt C;Li Y;Lin DT
通讯作者：
Lin DT
影响因子：
3.5
作者：
Janssens J;Van Broeckhoven C
通讯作者：
Van Broeckhoven C
影响因子：
15.9
作者：
Igaz, Lionel M.;Kwong, Linda K.;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
影响因子：
8.6
作者：
Kovacs, Gabor G.;Murrell, Jill R.;Spina, Salvatore
通讯作者：
Spina, Salvatore