title: The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations.
abstract: Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous ((31)P) and proton ((1)H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA K(i) values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = -0.784, p = 0.008) and GPC concentrations (r = -0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance.
authors.affiliation: Department of Neurology, Goethe-University, Frankfurt/Main, Germany. hilker@med.uni-frankfurt.de
authors.forename: Rüediger
authors.initials: R
authors.lastname: Hilker
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pilatus
authors.forename: Carsten
authors.initials: C
authors.lastname: Eggers
authors.forename: Johann
authors.initials: J
authors.lastname: Hagenah
authors.forename: Julia
authors.initials: J
authors.lastname: Roggendorf
authors.forename: Simon
authors.initials: S
authors.lastname: Baudrexel
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Klein
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
authors.forename: Gereon R
authors.initials: GR
authors.lastname: Fink
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
mesh_terms: D004298:Dopamine / Q000378:metabolism*; D004734:Energy Metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase