Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Aberrant neuronal translation contributes to brain disorders.
• mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling controls translation.
• Fragile X syndrome (FXS), a cause of autism spectrum disorder (ASD), involves exaggerated neuronal translation.

Purpose of the Study:

• To investigate the therapeutic potential of S6K1 inhibitors in FXS.
• To assess the ability of S6K1 inhibitors to normalize translational homeostasis and disease phenotypes in FXS mouse models.

Main Methods:

• Utilized two S6K1 inhibitors: PF-4708671 and FS-115.
• Administered inhibitors to FXS model mice.
• Evaluated effects on protein synthesis, social behavior, cognitive flexibility, dendritic spine morphology, and physical characteristics.

Main Results:

• Both inhibitors reversed exaggerated protein synthesis, social deficits, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism in FXS mice.
• Pharmacokinetic profiles and efficacy in specific behaviors (marble burying, weight gain) varied between inhibitors.
• Demonstrated in vivo pharmacological effects of S6K1 inhibition in a relevant disease model.

Conclusions:

• S6K1 inhibitors show promise for treating FXS and potentially other neuropsychiatric disorders with aberrant mTORC1-S6K1 signaling.
• Targeting S6K1 offers a novel therapeutic strategy for conditions characterized by faulty protein synthesis.
• Further research is warranted to optimize S6K1 inhibitor therapy for neurological conditions.