Promoting Axon Regeneration in Adult CNS by Targeting Liver Kinase B1

Abstract

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 AMPKa, 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.

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

“…Apart from primary injury, neurons are particularly susceptible to secondary molecular events after SCI, including oxidative stress and cell apoptosis. Due to the poor regenerative capacity of neurons, inhibition of the secondary response after SCI to maintain neuron survival is a potential strategy for recovery after SCI ( Wang et al, 2018 ; Li et al, 2019 ; Ohtake et al, 2019 ). In the present study, we observed that the expression of Brd4 increased around lesion sites after SCI, primarily in neurons.…”

ANXA1 directs Schwann cells proliferation and migration to accelerate nerve regeneration through the FPR2/AMPK pathway

“…20,32 A previous study reported that AMPKα1 activation promoted axon regeneration by enhancing the growth capacity of mature neurons. 18 AMPK induced by insulin-like growth factor-1 improved mitochondrial function to drive axonal outgrowth. 46 Under stress conditions such as energy depletion, the AMPK F I G U R E 5 ANXA1 promoted SC proliferation and remyelination in vivo.…”

“…17 A recent study showed that regeneration of corticospinal axons was dramatically enhanced via the AMPK pathway. 18 Another report revealed the complex role of AMPK in positive regulation of myelin growth. 19 In addition, ANXA1-activated FPR2 receptors and the downstream AMPK signaling cascade, leading to regeneration of muscle fibers.…”

Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury

“…The physiological progression of SCI is characterized by a series of secondary molecular events including inflammatory response, mitochondrial dysfunction and oxidative stress, axonal demyelination, which cause neuron death and injury beyond the initial mechanical damage [2]. Despite there is yet no completely satisfactory therapy for the treatment of SCI in clinical trials, separately or combined targeting these secondary reactions have been regarded as proper therapeutic strategies and promoted functional recovery in almost animal cases [3][4][5][6].…”