The bioenergetic status relates to dopamine neuron loss in familial PD with PINK1 mutations

  • 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 (31P) and proton (1H) 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 Ki 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.

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Author:Rüdiger HilkerGND, Ulrich PilatusORCiD, Carsten Eggers, Johann Meinert HagenahGND, Julia Roggendorf, Simon BaudrexelGND, Johannes Christian Klein, Bernd Neumaier, Gereon Rudolf Fink, Helmuth SteinmetzORCiDGND, Christine Klein, Elke HattingenORCiDGND
URN:urn:nbn:de:hebis:30:3-275235
DOI:https://doi.org/10.1371/journal.pone.0051308
ISSN:1932-6203
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/23251494
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2012/12/10
Date of first Publication:2012/12/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2012/11/30
Volume:7
Issue:12: e51308
Page Number:7
Note:
Licensed under a Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.5/
HeBIS-PPN:314283501
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 3.0