Beyond Trophic Factors: Exploiting the Intrinsic Regenerative Properties of Adult Neurons

Abstract

Injuries and diseases of the peripheral nervous system (PNS) are common but frequently irreversible. It is often but mistakenly assumed that peripheral neuron regeneration is robust without a need to be improved or supported. However, axonal lesions, especially those involving proximal nerves rarely recover fully and injuries generally are complicated by slow and incomplete regeneration. Strategies to enhance the intrinsic growth properties of reluctant adult neurons offer an alternative approach to consider during regeneration. Since axons rarely regrow without an intimately partnered Schwann cell (SC), approaches to enhance SC plasticity carry along benefits to their axon partners. Direct targeting of molecules that inhibit growth cone plasticity can inform important regenerative strategies. A newer approach, a focus of our laboratory, exploits tumor suppressor molecules that normally dampen unconstrained growth. However several are also prominently expressed in stable adult neurons. During regeneration their ongoing expression “brakes” growth, whereas their inhibition and knockdown may enhance regrowth. Examples have included phosphatase and tensin homolog deleted on chromosome ten (PTEN), a tumor suppressor that inhibits PI3K/pAkt signaling, Rb1, the protein involved in retinoblastoma development, and adenomatous polyposis coli (APC), a tumor suppressor that inhibits β-Catenin transcriptional signaling and its translocation to the nucleus. The identification of several new targets to manipulate the plasticity of regenerating adult peripheral neurons is exciting. How they fit with canonical regeneration strategies and their feasibility require additional work. Newer forms of nonviral siRNA delivery may be approaches for molecular manipulation to improve regeneration.

Schwann Cell Role in Selectivity of Nerve Regeneration

“…Plenty of studies have been performed on treatments to improve axonal regeneration after peripheral nerve injury, either by administering different drugs, adding trophic factors, gene therapy approaches, applying activity-dependent therapies or increasing the intrinsic growth capability of neurons (reviewed in [ 2 , 18 , 19 , 20 , 21 ]). However, the impact of these strategies on accurate reinnervation and functional recovery is usually limited.…”

Signals Orchestrating Peripheral Nerve Repair

“…These studies have provided insights into how 'sleeping' intrinsic growth activity can be reactivated in adult neurons, i.e., by down-regulation of genes encoding for neuronal activity (ion channels, synaptic proteins) [23], and up-regulation of growth-associated genes and related transcription factors, the so-called RAGs (regeneration-associated genes) [4], normally repressed by target-derived signals [24,25]. This has paved the way for manipulation of intrinsic programs to force nerve regeneration [25,26].…”

Simultaneous Knockdown of Sprouty2 and PTEN Promotes Axon Elongation of Adult Sensory Neurons

“…Successful regeneration is dependent on extrinsic factors in the environment as well as on the intrinsic regenerative capabilities of neurons. One reason for the limitations in peripheral nerve regeneration is the presence of intracellular inhibitors of neuronal growth factor signaling (Duraikannu et al, 2019). Among them are Sprouty2 (Spry2) and the dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which act as key regulators of receptor tyrosine kinase (RTK) signaling.…”