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Napoli E, Ross-Inta C, Song G, et al. Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding. Front Neurosci. 2016;10:159doi: 10.3389/fnins.2016.00159.
Napoli, E., Ross-Inta, C., Song, G., Wong, S., Hagerman, R., Gane, L. W., Smilowitz, J. T., Tassone, F., & Giulivi, C. (2016). Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding. Frontiers in neuroscience, 10159. https://doi.org/10.3389/fnins.2016.00159
Napoli, Eleonora, et al. "Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding." Frontiers in neuroscience vol. 10 (2016): 159. doi: https://doi.org/10.3389/fnins.2016.00159
Napoli E, Ross-Inta C, Song G, Wong S, Hagerman R, Gane LW, Smilowitz JT, Tassone F, Giulivi C. Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding. Front Neurosci. 2016 Apr 19;10:159. doi: 10.3389/fnins.2016.00159. eCollection 2016. PMID: 27147951; PMCID: PMC4835505.
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Front Neurosci. 2016 Apr 19;10:159. doi: 10.3389/fnins.2016.00159. eCollection 2016.

Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding.

Frontiers in neuroscience

Eleonora Napoli, Catherine Ross-Inta, Gyu Song, Sarah Wong, Randi Hagerman, Louise W Gane, Jennifer T Smilowitz, Flora Tassone, Cecilia Giulivi

Affiliations

  1. Department of Molecular Biosciences, School of Veterinary Medicine Davis, CA, USA.
  2. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, DavisDavis, CA, USA; Department of Pediatrics, University of California Davis Medical CenterSacramento, CA, USA.
  3. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis Davis, CA, USA.
  4. Department of Food Science and Technology and Foods for Health Institute, University of California, Davis Davis, CA, USA.
  5. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, DavisDavis, CA, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, DavisDavis, CA, USA.
  6. Department of Molecular Biosciences, School of Veterinary MedicineDavis, CA, USA; Medical Investigations of Neurodevelopmental Disorders Institute, University of California, DavisDavis, CA, USA.

PMID: 27147951 PMCID: PMC4835505 DOI: 10.3389/fnins.2016.00159

Abstract

Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent β-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.

Keywords: FMR1; Shank3; bioenergetics; brain; milk; mitochondria; premutation; zinc

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