Promoting Axon Regeneration in Adult CNS by Targeting Liver Kinase B1
Autor: | Xinpei Jiang, George M. Smith, Shin-ichi Muramatsu, Armin Sami, Makoto Horiuchi, Lena Ma, Shuxin Li, Yosuke Ohtake, Kieran Slattery, Michael E. Selzer |
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Rok vydání: | 2019 |
Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Neurogenesis AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biology Serotonergic Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Drug Discovery Genetics medicine Animals Axon skin and connective tissue diseases Molecular Biology Spinal cord injury Spinal Cord Injuries PI3K/AKT/mTOR pathway 030304 developmental biology Pharmacology 0303 health sciences Tyrosine hydroxylase Kinase Regeneration (biology) Recovery of Function medicine.disease Spinal cord Axons Nerve Regeneration Cell biology Disease Models Animal medicine.anatomical_structure 030220 oncology & carcinogenesis Molecular Medicine Original Article |
Zdroj: | Molecular Therapy. 27:102-117 |
ISSN: | 1525-0016 |
Popis: | Liver kinase B1 (LKB1), a downstream effector of cyclic AMP (cAMP)/PKA and phosphatidylinositol 3-kinase (PI3K) pathways, is a determinant for migration and differentiation of many cells, but its role in CNS axon regeneration is unknown. Therefore, LKB1 was overexpressed in sensorimotor cortex of adult mice five days after mid-thoracic spinal cord injury, using an AAV2 vector. Regeneration of corticospinal axons was dramatically enhanced. Next, systemic injection of a mutant-AAV9 vector was used to upregulate LKB1 specifically in neurons. This promoted long-distance regeneration of injured corticospinal fibers into caudal spinal cord in adult mice and regrowth of descending serotonergic and tyrosine hydroxylase immunoreactive axons. Either intracortical or systemic viral delivery of LKB1 significantly improved recovery of locomotor functions in adult mice with spinal cord injury. Moreover, we demonstrated that LKB1 used AMPKα, NUAK1, and ERK as the downstream effectors in the cortex of adult mice. Thus, LKB1 may be a critical factor for enhancing the growth capacity of mature neurons and may be an important molecular target in the treatment of CNS injuries. |
Databáze: | OpenAIRE |
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