title: Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Dr., VetMed 3B, Davis, CA, 95616, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Dr., VetMed 3B, Davis, CA, 95616, USA.
authors.forename: Gyu
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Dr., VetMed 3B, Davis, CA, 95616, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders Institute (M. I. N. D.), University of California Davis, Sacramento, CA, 95817, USA.|Department of Pediatrics, University of California Medical Center, Sacramento, CA, 95817, USA.
authors.forename: Randi
authors.initials: R
authors.lastname: Hagerman
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Dr., VetMed 3B, Davis, CA, 95616, USA. cgiulivi@ucdavis.edu.|Medical Investigation of Neurodevelopmental Disorders Institute (M. I. N. D.), University of California Davis, Sacramento, CA, 95817, USA. cgiulivi@ucdavis.edu.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002950:Citrate (si)-Synthase / Q000378:metabolism; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D058068:Endophenotypes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D062706:Prodromal Symptoms; D014202:Tremor / Q000378:metabolism* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D055815:Young Adult
chemical_list: D000255:Adenosine Triphosphate; D015415:Biomarkers; D002950:Citrate (si)-Synthase; D051860:Fragile X Messenger Ribonucleoprotein 1; D010100:Oxygen; C497683:FMR1 protein, human
keywords: Autism; Endophenotyes; Fragile X; Mitochondria; Mitochondrial network; Neurodegeneration; Premutation; Triplet nucleotide diseases