Traumatic brain injury induces TDP-43 mislocalization and neurodegenerative effects in tissue distal to the primary injury site in a non-transgenic mouse.
Traumatic brain injury induces TDP-43 mislocalization and neurodegenerative effects in tissue distal to the primary injury site in a non-transgenic mouse.
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DOI：
10.1186/s40478-023-01625-7
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发表时间：
2023-08-22
影响因子：
7.1
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中科院分区：
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创伤性脑损伤（TBI）引发脑组织和细胞损伤，随后立即发生具有延迟和持续损伤的继发性损伤后遗症。这种继发性损伤包括可能导致慢性神经变性和永久性功能和认知缺陷的病理过程。TBI还与发展神经退行性疾病的风险增加相关，如阿尔茨海默病（AD）、额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS），如由共同的病理特征所指示的。例如，TAR DNA结合蛋白43（TDP-43）异常，包括细胞质错误定位、胞质聚集以及磷酸化和泛素化增加，见于高达50%的FTD病例和高达70%的AD病例，被认为是ALS的标志性病理学，发生在> 97%的病例中。然而，TBI后TDP-43病理学的患病率尚未完全表征。在这里，我们采用了非转基因小鼠控制的TBI皮质损伤模型，并观察到在原发性损伤部位远端的脑和脊髓组织中损伤诱导的标志性TDP-43病理学，并且不包括原发性皮质损伤部位内的局灶性损伤组织。分析显示，时间依赖性和显着增加的神经元TDP-43错误定位在皮质前脑喙和远离原发性损伤部位损伤后180天（DPI）。TDP-43的错误定位也检测到位于颈脊髓腹角的神经元TBI后。此外，确定了皮质层依赖性影响，从7 DPI到180 DPI，随着时间的推移，从表层到深层皮质层增加。最后，RNAseq分析证实了与神经元有关的几个关键生物过程的损伤诱导的失调，这些过程随着时间的推移而增加。总的来说，这项研究证明了一个单一的中度TBI事件和慢性神经退行性过程，不限于原发性损伤部位和广泛分布在整个皮质和皮质脊髓束之间的连接。在线版本包含补充材料，可通过10.1186/s40478-023-01625-7获得。
Traumatic brain injury (TBI) initiates tissue and cellular damage to the brain that is immediately followed by secondary injury sequalae with delayed and continual damage. This secondary damage includes pathological processes that may contribute to chronic neurodegeneration and permanent functional and cognitive deficits. TBI is also associated with an increased risk of developing neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) as indicated by shared pathological features. For example, abnormalities in the TAR DNA-binding Protein 43 (TDP-43) that includes cytoplasmic mislocalization, cytosolic aggregation, and an increase in phosphorylation and ubiquitination are seen in up to 50% of FTD cases, up to 70% of AD cases, and is considered a hallmark pathology of ALS occurring in > 97% of cases. Yet the prevalence of TDP-43 pathology post-TBI has yet to be fully characterized. Here, we employed a non-transgenic murine controlled cortical injury model of TBI and observed injury-induced hallmark TDP-43 pathologies in brain and spinal cord tissue distal to the primary injury site and did not include the focally damaged tissue within the primary cortical injury site. Analysis revealed a temporal-dependent and significant increase in neuronal TDP-43 mislocalization in the cortical forebrain rostral to and distant from the primary injury site up to 180 days post injury (DPI). TDP-43 mislocalization was also detected in neurons located in the ventral horns of the cervical spinal cord following a TBI. Moreover, a cortical layer-dependent affect was identified, increasing from superficial to deeper cortical layers over time from 7 DPI up to 180 DPI. Lastly, RNAseq analysis confirmed an injury-induced misregulation of several key biological processes implicated in neurons that increased over time. Collectively, this study demonstrates a connection between a single moderate TBI event and chronic neurodegenerative processes that are not limited to the primary injury site and broadly distributed throughout the cortex and corticospinal tract. The online version contains supplementary material available at 10.1186/s40478-023-01625-7.
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