Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets

Abstract

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.

What Is the Role of the Rho-ROCK Pathway in Neurologic Disorders?

“…Studies in experimental disease models emphasized the neuroprotective effects of ROCK inhibitors such as fasudil in experimental models of these and other disorders. [4][5][6][7][8]31,78,81,88,99,100 Only few examples will be emphasized in this study. ROCK2 levels are increased in postmortem tissue at the earliest stages of AD and remain elevated throughout disease progression.…”

“…Rho/ROCK signaling is a major effector of multiple signals that prevent axonal growth and regeneration in the central nervous system after injury. 31 When myelinated axons are damaged, they are exposed to myelin debris that contain inhibitory molecules for axonal regrowth, including Nogo, myelin-associated glycoprotein and oligodendrocyte-myelin glycoprotein. 31 These proteins bind to the Nogo receptor (NgR), which forms a complex with the leucine-rich repeat and Ig domain–containing 1 protein 37 and with either the low-affinity neurotrophin receptor p75 NTR38 or the tumor necrosis factor receptor orphan Y (TROY) 39 to activate the RhoA/ROCK pathway and inhibit axonal growth.…”

“…21 The effects of Rho/ROCK signaling on the cytoskeleton have a major role in the developing and adult nervous system, both in normal and pathologic conditions. These include closure of the neural tube, 27,28 migration of neuronal precursor cells, 29 inhibition of neurite growth during development, 30 impaired axonal regeneration after injury, 4,31 dendritic formation, 32 dendritic spine structural plasticity, 33 stress fiber assembly and cell adhesion, 34 destabilization of endothelial cell junctions, 35 and execution phases of apoptosis, including cell membrane contraction, membrane blebbing, nuclear disintegration, and fragmentation of apoptotic cells. 25,36…”

Abnormal intraepidermal nerve fiber density in disease: A scoping review

“…When damaged, peripheral nerves can degenerate and later regenerate to restore function to peripheral tissues ( 1 ). Successful regeneration requires sophisticated communication between glial cells, vascular components, connective tissues, and the immune system ( 2 , 3 ) and is dependent on energetic states ( 4–10 ). New information is emerging related to the molecular signals required for what is now recognized as active processes leading to the degeneration of peripheral axons, including sterile alpha and TIR motif containing 1 (SARM1) and other potential mediators ( 11–14 ).…”

Abnormal Intraepidermal Nerve Fiber Density in Disease: A Scoping Review

“…When damaged, peripheral nerves can degenerate and later regenerate to restore function to peripheral tissues [1]. Successful regeneration requires sophisticated communication between glial cells, vascular components, connective tissues, and the immune system [2,3] and is dependent on energetic states [4][5][6][7][8][9][10]. New information is emerging related to the molecular signals required for what is now recognized as active processes leading to the degeneration of peripheral axons, including sterile alpha and TIR motif containing 1 (SARM1) and other potential mediators [11][12][13][14].…”