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Abstract
BackgroundParkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.Methodology/Principal FindingsNow we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of α-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.ConclusionThus, aging Pink1−/− mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
Highlights
Parkinson’s disease (PD) is diagnosed mostly in elderly people by clinical criteria, based on a typical progressive reduction of their spontaneous movement activity in spite of preserved strength and coordination
Conclusion: aging Pink12/2 mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death
To assess whether the intense smaller band detected by Northern blot represents a Pink1 isoform, quantitative real time reverse transcriptase (RT)-PCR (qPCR) analysis of Pink1 mRNA sequences on both sides of the Neo insertion site were performed and showed a 97% reduction in homozygous mutant brain tissue in both cases, indicating that the smaller band in Northern is due to unspecific cross-hybridization (Fig. 1E)
Summary
Parkinson’s disease (PD) is diagnosed mostly in elderly people by clinical criteria, based on a typical progressive reduction of their spontaneous movement activity in spite of preserved strength and coordination. Previous studies of Pink knock-out (KO) mouse brain reported (1) elevated susceptibility to H2O2 or heat-shock with decreased activities of the oxidative-stress vulnerable respiratory complexes as well as aconitase [14], (2) increased calcium levels and vulnerability with subsequent excess ROS production, decreased glucose availability and loss of mitochondrial membrane potential to cause pathological opening of the mitochondrial permeability transition pore [15], (3) reduced synaptic dopamine release and plasticity in the striatum [16], (4) sensitization to activation of group II metabotropic glutamate receptors at corticostriatal synapses [17] and (5) reduced viability of cortical neuron cultures [18] It remained unclear, whether essential mitochondrial functions such as preprotein import and fission/fusion are maintained in the mice, whether the mitochondrial and synaptic dysfunction progress with age to impair movement and behaviour and whether a neurodegenerative process with a-synuclein aggregation is initiated. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD
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