The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury

Abstract

Themammaliantarget of rapamycin(mTOR)positively regulatesaxongrowth in themammaliancentral nervous system (CNS). Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 inCNSneurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3mmbeyond the injury site at 8 weeks after injury. Concomitantly, treatment withPF-4708671producedsignificantlocomotorrecovery. Pharmacological targeting ofS6K1maytherefore constituteanattractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.