ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.,Nature Neuroscience

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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2019-Jan-14 , DOI: 10.1038/s41593-018-0300-4
Joseph R Klim _{1,

2,

3,

4} , Luis A Williams _{1,

2,

3,

4,

5} , Francesco Limone _{1,

2,

3,

4,

6} , Irune Guerra San Juan _{1,

2,

3,

4,

7} , Brandi N Davis-Dusenbery _{1,

2,

3,

4,

8} , Daniel A Mordes _{1,

2,

3,

4,

9} , Aaron Burberry _{1,

2,

3,

4} , Michael J Steinbaugh ₁₀ , Kanchana K Gamage _{1,

2,

3,

4,

11} , Rory Kirchner ₁₀ , Rob Moccia _{1,

2,

3,

4,

12} , Seth H Cassel _{1,

2,

3,

4,

13,

14} , Kuchuan Chen ₁₅ , Brian J Wainger _{15,

16} , Clifford J Woolf ₁₅ , Kevin Eggan _{1,

2,

3,

4}

Affiliation

Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Q-State Biosciences, Cambridge, MA, USA.
Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Seven Bridges Genomics, Cambridge, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Amgen Research, Amgen, Inc., Cambridge, MA, USA.
Pfizer, Inc., Cambridge, MA, USA.
Harvard Medical School, Boston, MA, USA.
Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA.
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.

中文翻译：

ALS 相关蛋白 TDP-43 维持 STMN2 的水平，STMN2 是运动神经元生长和修复的介质。

肌萎缩侧索硬化症 (ALS) 患者几乎普遍表现出 RNA 结合蛋白 TDP-43 的病理性错误定位，并且其基因突变导致家族性 ALS，这些发现已将 RNA 代谢改变命名为一种疾病机制。然而，运动神经元中 TDP-43 调节的 RNA 及其与神经病变的关系仍有待确定。在这里，我们报告了人类运动神经元中丰度对 TDP-43 耗竭敏感的转录本。值得注意的是，编码微管调节因子的 STMN2 的表达在 TDP-43 敲低和 TDP-43 错误定位后以及患者特异性运动神经元和死后患者脊髓中的表达下降。 TDP-43 功能降低导致 STMN2 丢失是由于剪接改变，这在功能上很重要，因为我们表明 STMN2 对于正常轴突生长和再生是必需的。值得注意的是，STMN2 的翻译后稳定可挽救 TDP-43 耗竭引起的神经突生长和轴突再生缺陷。我们建议将恢复 STMN2 表达作为 ALS 的治疗策略进行检查。

更新日期：2019-01-26

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