Defective RNA metabolism in motor neurons from Amyotrophic Lateral Scelosis patients

肌萎缩侧索硬化症患者运动神经元的 RNA 代谢缺陷

• 批准号: 23700455
• 负责人: TSUIJI Hitomi
• 金额: $ 2.75万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23700455/
• 关键词: ALS; spliceosome; snRNP; TDP-43; RNA; スプライソソーム; snRNA; SMN; SMA; FUS; RNA代謝; 筋萎縮性側索硬化症; 脊髄性筋萎縮症; splicing

Neurodegenerative diseases are characterized by the death of specific type of neurons. The motor neuron diseases amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are caused by dysfunction of TDP-43, RNA-binding protein and SMN, essential for biogenesis of spliceosomal component snRNPs, respectively. However, the defects in RNA metabolism common to these diseases remain unclear. We show that TDP-43 localizes in nuclear gems through association with the SMN complex, and is involved in spliceosome maintenance. Moreover, gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in the nuclei of ALS motor neurons but not in the temporal lobe of FTLD with TDP-43 pathology. Together, these findings indicate that collapse of spliceosome stability is the critical process common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.

神经退行性疾病的特征是特定类型的神经元死亡。运动神经元疾病肌萎缩侧索硬化症(ALS)和脊髓性肌萎缩症(SMA)分别由剪接体成分SnRNPs生物发生所必需的TDP-43、RNA结合蛋白和SMN功能障碍引起。然而，这些疾病常见的RNA代谢缺陷仍不清楚。我们发现TDP-43通过与SMN复合体结合定位于核宝石中，并参与剪接体的维持。此外，在TDP-43病理的FTLD中，GEM丢失，U-SnRNA水平上调，剪接体U-SnRNPs异常并广泛聚集在ALS运动神经元的核中，而在FTLD的颞叶中未见聚集。综上所述，这些发现表明剪接体稳定性的崩溃是ALS和SMA中常见的神经退变的关键过程，并可能解释运动神经元的细胞类型特异性脆弱性。

项目成果

Spliceosome Integrity is a Common Target for Motor Neuron Disease

剪接体完整性是运动神经元疾病的常见目标

• 发表时间: 2012
• 作者: 芝崎真裕;大熊誠太郎;Tsuiji H. and Yamanaka K
• 通讯作者: Tsuiji H. and Yamanaka K

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Regulation of spliceosome by ALS-causative gene TDP-43

ALS 致病基因 TDP-43 对剪接体的调节

• 发表时间: 2011
• 作者: Tsuiji H.;Kataoka A.;Yamanaka K
• 通讯作者: Yamanaka K

A Role of TDP-43 in The Regulation of spliceosomal U snRNPs

TDP-43 在剪接体 U snRNP 调节中的作用

• 发表时间: 2011
• 作者: Tsuiji H.;Kataoka A.;Yamanaka K
• 通讯作者: Yamanaka K

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