PTEN inhibition and axon regeneration and neural repair

Abstract

The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog (PTEN) appears critical to control the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in conditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Importantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.

Keywords: PTEN inhibition; antagonist peptide; axon regeneration; functional recovery; intrinsic growth capacity; spinal cord injury.

Figure 1

Schematic of Akt/PTEN pathway that regulates neuronal growth and axon regeneration by PTEN inhibition. Various growth factors, such as nerve growth factor, activate their receptors (especially the tyrosine receptor kinases (TRK)) and PI3K pathway and stimulate neuronal growth by enchaining mTOR activity and suppressing GSK-3β signal. In contrast, intracellular PTEN phos-phatase blocks axon growth by inactivating Akt signal and mTOR path-way. PTEN inhibition by a number of approaches, including deletion in knockout (KO) mice, knockdown by shRNA, or pharmacological blockade with phosphatase inhibitor bpV or selective antagonists PTEN antagonist peptides, promotes neuronal regeneration. PTEN: Phosphatase and tensin homolog; 4E-BP: 4E-binding protein; bpV: bisperoxovanadium; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 3,4,5 trisphosphate; PI3K: phosphoinositide 3-kinase; GSK-3β: glycogen synthase kinase 3β; S6K: S6 kinase; PAPs: PTEN antagonist peptides.