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

Hassan Al-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao-Ming Xu, Vance P. Lemmon, John L. Bixby

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7079-7095
Number of pages17
JournalJournal of Neuroscience
Volume37
Issue number30
DOIs
StatePublished - Jul 26 2017

Fingerprint

Ribosomal Protein S6 Kinases
Nervous System Trauma
Axons
Regeneration
Pharmaceutical Preparations
Wounds and Injuries
Pyramidal Tracts
Sirolimus
Growth
Phosphatidylinositol 3-Kinases
Nervous System
Clinical Trials
Pharmacology
Genes

Keywords

  • Axon regeneration
  • Drug discovery
  • Drug target
  • Kinase
  • S6K
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury. / Al-Ali, Hassan; Ding, Ying; Slepak, Tatiana; Wu, Wei; Sun, Yan; Martinez, Yania; Xu, Xiao-Ming; Lemmon, Vance P.; Bixby, John L.

In: Journal of Neuroscience, Vol. 37, No. 30, 26.07.2017, p. 7079-7095.

Research output: Contribution to journalArticle

Al-Ali, Hassan ; Ding, Ying ; Slepak, Tatiana ; Wu, Wei ; Sun, Yan ; Martinez, Yania ; Xu, Xiao-Ming ; Lemmon, Vance P. ; Bixby, John L. / The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 30. pp. 7079-7095.
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