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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 (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.
Highlights
Mutations of the PTEN-induced putative kinase 1 (PINK1) gene mapped to chromosome 1p36 (PARK6) were reported in up to 5% of patients with autosomal recessive Parkinson’s disease (PD) [1,2]
In order to investigate the pathophysiology of PINK1-associated PD in a large German family with a PINK1 nonsense mutation (c.1366C.T; p.Q456X), we performed combined phosphorous (31P) and proton (1H) magnetic resonance spectroscopic imaging (MRSI) on a 3-Tesla scanner in 11 family members who already had participated in a prior study with 18-Fluorodopa (FDOPA) positron emission tomography (PET) [10]
The MRSI findings in heterozygous family members with a mild dopaminergic dysfunction in FDOPA PET suggest that heterozygous loss-of-function is associated with a normal level of high-energy phosphates in mesostriatal brain tissue
Summary
Mutations of the PTEN-induced putative kinase 1 (PINK1) gene mapped to chromosome 1p36 (PARK6) were reported in up to 5% of patients with autosomal recessive Parkinson’s disease (PD) [1,2]. Recent studies on fibroblasts from PD patients with endogenous expression of mutant PINK1 pointed to respiratory chain deficiencies and enhanced production of reactive oxygen species (ROS), but yielded heterogenous data on cellular. ATP levels, activity of respiratory chain enzymes and antioxidant defense mechanisms [6,7,8,9]. The graded severity of striatal FDOPA loss in this cohort with either a single or two mutated PINK1 alleles allowed for correlating individual findings of metabolic brain mapping in MRSI with previously obtained PET data.
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