Modulation of mitochondrial efficiency to treat fragile X syndrome

  • Awarded: 2017
  • Award Type: Pilot
  • Award #: 513123

Fragile X syndrome (FXS) is a devastating X-linked genetic disorder that is the most-common known cause of inherited intellectual disability. Its effects manifest themselves during the first few years of life, emphasizing the importance of early intervention to prevent aberrant brain development. One of the known functions of the fragile X mental retardation protein (FMRP) is as an RNA-binding protein that represses the translation of mRNAs whose protein products modulate synaptic function. Loss of FMR1, the gene-encoding FMRP, therefore leads to unregulated protein translation, abnormal synaptic plasticity and loss of normal learning in rodents and humans. In addition to this known function, Elizabeth Jonas recently found that FMRP is a mitochondrial regulatory protein that adjusts the efficiency of mitochondrial metabolism and thereby the rate of protein translation (unpublished data). These studies suggest a novel idea: that protein translation and synaptic plasticity in neuronal synapses are regulated by mitochondrial metabolism.

Mitochondria are a key producer of ATP, and the highest levels of ATP are found within a small space between the mitochondria and the endoplasmic reticulum/ribosomal complex. Decreased metabolic efficiency in the case of FMRP depletion results in lack of time-dependent phosphorylation events after synaptic activity, suggesting that ATP production within this small space between the mitochondria and the ER is inadequate. This may result in unregulated protein translation and inadequate synaptic plasticity.

To test this hypothesis, Jonas’s team plans to reverse abnormal phenotypes in FMR1 knockout mouse neurons by enhancing the efficiency of mitochondria. Jonas will enhance efficiency by closing a mitochondrial inner membrane leak channel contained within the membrane embedded portion of the ATP synthase (the enzyme that produces ATP). Her team proposes that genetic or pharmacological decrease of leak channel activity will normalize mitochondrial metabolism and protein translation, and will thereby enhance normal synaptic development during the crucial early stages of brain growth.

Jonas’s group will also study the role of mutagenesis of the ATP synthase leak channel in decreasing its conductance. In addition, they will evaluate whether the ATP synthase leak channel modulator dexpramipexole and a cyclosporine A analog (NIM811) — a known modulator of mitochondrial function — can rescue the metabolic, synaptic and learning abnormalities in FMR1 knockout mice.

If these studies are successful, Jonas’s team will participate in planning clinical trials of dexpramipexole in individuals with fragile X, as well as of novel therapeutic agents that are in development based on the mitochondrial targets recently discovered in their laboratory.

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