title: Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.
abstract: OBJECTIVE
  Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders.
  
  
  METHODS
  Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism.
  
  
  RESULTS
  The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood.
  
  
  CONCLUSIONS
  Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.
authors.affiliation: School of Psychological Science, La Trobe University, Melbourne, Victoria, Australia. d.loesch@latrobe.edu.au
authors.forename: Danuta Z
authors.initials: DZ
authors.lastname: Loesch
authors.forename: David E
authors.initials: DE
authors.lastname: Godler
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.forename: Quang M
authors.initials: QM
authors.lastname: Bui
authors.forename: Freya
authors.initials: F
authors.lastname: Gehling
authors.forename: Katya E
authors.initials: KE
authors.lastname: Kotschet
authors.forename: Nicholas
authors.initials: N
authors.lastname: Trost
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.forename: Paige
authors.initials: P
authors.lastname: Stimpson
authors.forename: Glynda
authors.initials: G
authors.lastname: Kinsella
authors.forename: David
authors.initials: D
authors.lastname: Francis
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Alison
authors.initials: A
authors.lastname: Venn
authors.forename: Howard R
authors.initials: HR
authors.lastname: Slater
authors.forename: Malcolm
authors.initials: M
authors.lastname: Horne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger