Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing.,Cell Death and Differentiation

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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-04-27 , DOI: 10.1038/s41418-020-0543-y
Björn Friedhelm Vahsen ₁ , Vinicius Toledo Ribas ₂ , Jonas Sundermeyer ₁ , Alexander Boecker ₃ , Vivian Dambeck _{1,

4,

5} , Christof Lenz _{6,

7} , Orr Shomroni ₈ , Lucas Caldi Gomes ₁ , Lars Tatenhorst _{1,

4,

5} , Elisabeth Barski ₁ , Anna-Elisa Roser _{1,

5} , Uwe Michel ₁ , Henning Urlaub _{6,

7} , Gabriela Salinas ₈ , Mathias Bähr _{1,

5} , Jan Christoph Koch _{1,

5} , Paul Lingor _{1,

4,

5,

9}

Affiliation

Department of Neurology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Department of Morphology, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 630 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA, 19104, USA.
Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
DFG Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Institute of Clinical Chemistry, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.
NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077, Göttingen, Germany.
Department of Neurology, Rechts der Isar Hospital, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

中文翻译：

自噬蛋白 ULK1 的抑制在体外和体内减弱轴突变性，增强翻译，并调节剪接。

轴索变性是中枢神经系统创伤性和神经退行性疾病的关键和早期病理特征。在轴突发生局灶性病变后，急性轴索变性 (AAD) 会在数小时内发生延长的轴突崩解。在 AAD 期间，包括 Unc-51 在内的自噬蛋白的积累已被证明，如自噬激活激酶 1 (ULK1)，但其作用尚不完全清楚。在这里，我们研究了 ULK1 抑制在体外和体内损伤诱导的轴突变性的不同模型中的作用。在原代大鼠皮层神经元中过表达 ULK1 (ULK1.DN) 的显性阴性在体外减弱了轴突切开诱导的 AAD。ULK1.DN 和 ULK1 抑制剂 SBI-0206965 均可在体内大鼠视神经压伤后预防 AAD。ULK1。DN 在体内还可减轻大鼠脊髓损伤后的长期轴突变性。从机制上讲，ULK1.DN 会降低自噬并导致 mTOR 介导的翻译蛋白增加。始终如一地，用 SBI-0206965 治疗会导致 mTOR 激活增强。ULK1.DN 还调节变性相关基因 Kif1b 和 Ddit3 的差异剪接。这些发现揭示了 ULK1 作为体外和体内轴突变性的重要介质，并阐明了其在剪接中的功能，将其定义为推定的治疗靶点。DN 还调节变性相关基因 Kif1b 和 Ddit3 的差异剪接。这些发现揭示了 ULK1 作为体外和体内轴突变性的重要介质，并阐明了其在剪接中的功能，将其定义为推定的治疗靶点。DN 还调节变性相关基因 Kif1b 和 Ddit3 的差异剪接。这些发现揭示了 ULK1 作为体外和体内轴突变性的重要介质，并阐明了其在剪接中的功能，将其定义为推定的治疗靶点。

更新日期：2020-04-27

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