Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Fragile X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to expanded CGG repeats in the FMR1 gene's 5' UTR.
• The toxic gain-of-function from elevated mRNA is implicated in FXTAS pathogenesis.
• Previous studies suggested rapamycin, an autophagy inducer, could mitigate neurotoxicity in neurodegenerative diseases.

Purpose of the Study:

• To investigate the effect of rapamycin on FXTAS neurodegeneration induced by FMR1 5'UTR CGG90 repeats in Drosophila.
• To explore the role of autophagy and mammalian target of rapamycin (mTOR) signaling in FXTAS pathogenesis and potential therapeutic strategies.

Main Methods:

• Utilized a Drosophila model expressing human FMR1 5'UTR with 90 CGG repeats (rCGG90) to mimic FXTAS.
• Administered rapamycin to FXTAS flies and assessed neurodegenerative phenotypes.
• Analyzed CGG90 expression levels and investigated the impact of mTOR signaling activation on neurodegeneration.

Main Results:

• Rapamycin unexpectedly exacerbated rCGG90-induced neurodegeneration through an autophagy-independent mechanism.
• Rapamycin treatment did not significantly alter CGG90 expression levels in FXTAS flies.
• Activation of mTOR signaling demonstrated a protective effect against neurodegeneration in FXTAS models.

Conclusions:

• Enhancing autophagy is not a sufficient strategy to alleviate neurotoxicity in FXTAS.
• Rapamycin exacerbates FXTAS neurodegeneration, contrary to expectations based on other models.
• mTOR signaling and its downstream effectors represent promising therapeutic targets for FXTAS treatment.