少突胶质细胞中与 ALS 相关的突变体 TDP-43 会诱发少突胶质细胞损伤,并加剧小鼠的运动功能障碍。

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka
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引用次数: 0

摘要

43 kDa TAR DNA 结合蛋白(TDP-43)的核清除和胞质聚集是肌萎缩侧索硬化症(ALS)的病理特征,其致病机制是由 TDP-43 的功能缺失和毒性增益介导的。然而,TDP-43毒性增益在少突胶质细胞中的作用仍不清楚。为了研究过量的 TDP-43 对少突胶质细胞的影响,我们通过与 Mbp-Cre 小鼠杂交,建立了在少突胶质细胞中过表达与 ALS 相关的突变体 TDP-43M337V 的转基因小鼠。浮性 TDP-43M337V 小鼠与 Mbp-Cre 小鼠两步杂交后,TDP-43M337V 在少突胶质细胞特异性过表达的同时(Cre 阳性)或不表达(Cre 阴性),形成杂合子低水平系统表达。虽然 Cre 阴性小鼠也表现出微弱的运动功能障碍,但在 Cre 阳性小鼠中,少突胶质细胞中 TDP-43M337V 的过表达加剧了胼胝体和腰部脊髓白质中髓鞘苍白的抓握征和步态障碍。从 12 个月大的转基因小鼠全脑中分离出的少突胶质细胞系细胞的 RNA 序列分析显示,髓鞘化少突胶质细胞标志基因和对髓鞘化至关重要的胆固醇相关基因下调,同时凋亡通路基因明显上调。免疫荧光染色显示,在老化的转基因小鼠中,被活化的小胶质细胞和星形胶质细胞包围的凋亡少突胶质细胞的caspase 3裂解酶呈阳性。总之,我们的研究结果表明,与 ALS 相关的突变型 TDP-43 在少突胶质细胞中的过量表达会加剧小鼠的运动功能障碍,这可能是通过少突胶质细胞功能障碍和神经炎症引起的。因此,针对少突胶质细胞的保护,特别是通过改善 TDP-43 的病理变化,可能是 ALS 的一种潜在治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43M337V. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43M337V overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.

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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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