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  3. Lipin1 depletion coordinates neuronal signaling pathways to promote motor and sensory axon regeneration after spinal cord injury

Lipin1 depletion coordinates neuronal signaling pathways to promote motor and sensory axon regeneration after spinal cord injury

  • Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2404395121. doi: 10.1073/pnas.2404395121.
Weitao Chen # 1,  Junqiang Wu # 2,  Chao Yang # 2 3 4,  Suying Li 5 6 7 8,  Zhewei Liu 2,  Yongyan An 2,  Xuejie Wang 2 3,  Jiaming Cao 2,  Jiahui Xu 2 3 4,  Yangyang Duan 2 3 4,  Xue Yuan 3,  Xin Zhang 2,  Yiren Zhou 2,  Jacque Pak Kan Ip 9,  Amy K Y Fu 2 3 4,  Nancy Y Ip 2 3 4,  Zhongping Yao 5 6 7 8,  Kai Liu 1 2 3 4 10
Affiliations

Affiliations

  • 1 Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
  • 2 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 3 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • 4 Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, Hong Kong University of Science and Technology Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China.
  • 5 State Key Laboratory of Chemical Biology and Drug Discovery, Research Institute for Future Food, Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region, China.
  • 6 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region, China.
  • 7 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
  • 8 Shenzhen Key Laboratory of Food Biological Safety Control, Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
  • 9 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
  • 10 Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
  • # Contributed equally.
PMID: 39292743 DOI: 10.1073/pnas.2404395121
Abstract

Adult central nervous system (CNS) neurons down-regulate growth programs after injury, leading to persistent regeneration failure. Coordinated lipids metabolism is required to synthesize membrane components during axon regeneration. However, lipids also function as cell signaling molecules. Whether lipid signaling contributes to axon regeneration remains unclear. In this study, we showed that lipin1 orchestrates mechanistic target of rapamycin (mTOR) and STAT3 signaling pathways to determine axon regeneration. We established an mTOR-lipin1-phosphatidic acid/lysophosphatidic acid-mTOR loop that acts as a positive feedback inhibitory signaling, contributing to the persistent suppression of CNS axon regeneration following injury. In addition, lipin1 knockdown (KD) enhances corticospinal tract (CST) sprouting after unilateral pyramidotomy and promotes CST regeneration following complete spinal cord injury (SCI). Furthermore, lipin1 KD enhances sensory axon regeneration after SCI. Overall, our research reveals that lipin1 functions as a central regulator to coordinate mTOR and STAT3 signaling pathways in the CNS neurons and highlights the potential of lipin1 as a promising therapeutic target for promoting the regeneration of motor and sensory axons after SCI.

Keywords

axon regeneration; lipid metabolism; lipid signaling; lipin1; spinal cord injury.

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