Analysis of ?-Synuclein Pathology in PINK1 Knockout Rat Brains.

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 ?-synuclein. Previous studies of PINK1 knockout (PINK1-/-) rats have reported mitochondrial dysfunction, locomotor behavioral deficits, loss of neurons in the substantia nigra and ?-synuclein aggregates in various brain regions. We sought to characterize PINK1-/- rats in more detail specifically with respect to ?-synuclein pathology because abnormal ?-synuclein has been implicated genetically, biophysically and neuropathologically as a mechanism of PD pathogenesis. Moreover, the spontaneous formation of ?-synuclein aggregates without ?-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 ?-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 ?-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 ?-synuclein. Total synuclein protein levels were unchanged; however, biochemical fractionation showed a significant shift of ?-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 ?-synuclein localization, protease resistance and aggregation in vivo. The PINK1-/- rat could be a useful animal model to study the role of abnormal ?-synuclein in PD-related neurodegeneration.

SUBMITTER: Creed RB 

PROVIDER: S-EPMC6333903 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature