Abstract
The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson’s disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker β-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using β-galactosidase (β-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.
Highlights
Introduction αSynucleinopathies are neurodegenerative diseases characterized by misfolded α-synuclein aggregates, which are the major component of Lewy bodies in neurons and Lewy neurites in neuronal terminals [55, 69, 82]
Our results show that BSSG promotes the appearance and spreading of pathological α-synuclein aggregates, which were the primary cause of the death of dopaminergic neurons by inducing apoptosis and possibly senescence
Intracellular aggregates of αsynuclein were observed in the striatum, whereas Lewyneurite-like structures and intracellular aggregates were both observed in the Primary motor cortex (M1)-cortex (Fig. 2a,b)
Summary
Synucleinopathies are neurodegenerative diseases characterized by misfolded α-synuclein aggregates, which are the major component of Lewy bodies in neurons and Lewy neurites in neuronal terminals [55, 69, 82]. Of the three main types of α-synucleinopathy, Parkinson’s disease (PD) is the most common and pure αsynucleinopathy phenotype [29]. Human genetic evidence suggests that altered α-synuclein can cause the death of dopaminergic neurons and of other neuronal groups in the brain. SNCA duplications cause PD αsynucleinopathy by increasing normal α-synuclein levels in the midbrain [41]. Epidemiological studies have associated different polymorphisms around the SNCA with the lifetime risk of sporadic PD [47, 52], possibly by increasing native α-synuclein levels
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