Abstract
Mutations in PTEN induced kinase 1 (PINK1) cause autosomal recessive Parkinson’s disease (PD). The main pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of protein aggregates containing α-synuclein. Previous studies of PINK1 knockout (PINK1-/-) rats have reported mitochondrial dysfunction, locomotor behavioral deficits, loss of neurons in the substantia nigra and α-synuclein aggregates in various brain regions. We sought to characterize PINK1-/- rats in more detail specifically with respect to α-synuclein pathology because abnormal α-synuclein has been implicated genetically, biophysically and neuropathologically as a mechanism of PD pathogenesis. Moreover, the spontaneous formation of α-synuclein aggregates without α-synuclein overexpression, injection or toxin administration is a rare and important characteristic for an animal model of PD or other synucleinopathies, such as dementia with Lewy bodies and multiple system atrophy. We observed α-synuclein-immunoreactive aggregates in various brain regions of PINK1-/- rats including cortex, thalamus, striatum and ventral midbrain, but nowhere in wild-type (WT) rats. Co-immunofluorescence showed that the α-synuclein-immunoreactive aggregates are both thioflavin S and ubiquitin positive. Many cells in the brains of PINK1-/- rats but not WT rats contained protease-resistant α-synuclein. Total synuclein protein levels were unchanged; however, biochemical fractionation showed a significant shift of α-synuclein from the cytosolic fraction to the synaptic vesicle-enriched fraction of PINK1-/- brain homogenates compared to WT. This data indicates that PINK1 deficiency results in abnormal α-synuclein localization, protease resistance and aggregation in vivo. The PINK1-/- rat could be a useful animal model to study the role of abnormal α-synuclein in PD-related neurodegeneration.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder
Because α-synuclein immunoreactive protein aggregates are pathognomonic for PD, and because genetic, biochemical in vitro and in vivo studies suggest α-synuclein oligomerization or aggregation is linked to the underlying mechanisms of neurodegeneration in PD, we focused our analysis of PTEN induced kinase 1 (PINK1)−/− rats on characterizing the pattern and agedependence of α-synuclein immunoreactivity throughout the brain
We found a relative increase in α-synuclein levels in the synaptic vesicle-enriched fraction of PINK1−/− rat brain compared to WT (Figures 2H,I)
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Clinically, PD is defined by slowness of movement, rigidity, postural instability, gait abnormalities and tremor. Fox Foundation for Parkinson’s Research sponsored the generation and initial characterization of PINK1−/− rats as a model of loss-of-function PINK1 mutations causally linked to recessively inherited PD (Valente et al, 2004; Dave et al, 2014). The initial study reported significant motor deficits and age-dependent loss of dopamine neurons in the substantia nigra of PINK1−/− rats (Dave et al, 2014). Subsequent studies of the same line of PINK1−/− rats reported mitochondrial dysfunction, behavioral deficits, loss of neurons in the substantia nigra and locus coeruleus, neurochemical abnormalities and α-synuclein aggregates in various brain regions (Grant et al, 2015; KelmNelson et al, 2015, 2016, 2018; Pultorak et al, 2016; Stauch et al, 2016a,b; Villeneuve et al, 2016a,b). We sought to further characterize PINK1−/− rats with respect to α-synuclein pathology because spontaneous formation of α-synuclein aggregates (without α-synuclein overexpression or injection) is a rare and important feature of PD animal models and because α-synuclein aggregation has been implicated both genetically and biochemically as a mechanism of PD pathogenesis as well as a potential therapeutic target (Goldberg and Lansbury, 2000; Creed and Goldberg, 2018)
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