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Unilateral intranigral administration of ?-sitosterol ?-D-glucoside triggers pathological ?-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

ABSTRACT: The spreading and accumulation of ?-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of ?-sitosterol ?-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6??g BSSG/?L 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 ?-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker ?-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using ?-galactosidase (?-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 ?-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The ?-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 ?-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 ?-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of ?-synuclein pathology and validate anti-synucleinopathy therapies.

SUBMITTER: Soto-Rojas LO

PROVIDER: S-EPMC7178762 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

Soto-Rojas Luis O LO Martínez-Dávila Irma A IA Luna-Herrera Claudia C Gutierrez-Castillo María E ME Lopez-Salas Francisco E FE Gatica-Garcia Bismark B Soto-Rodriguez Guadalupe G Bringas Tobon María Elena ME Flores Gonzalo G Padilla-Viveros America A Bañuelos Cecilia C Blanco-Alvarez Víctor Manuel VM Dávila-Ayala José J Reyes-Corona David D Garcés-Ramírez Linda L Hidalgo-Alegria Oriana O De La Cruz-López Fidel F Martinez-Fong Daniel D

Acta neuropathologica communications 20200422 1

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 ...[more]

PMID: 32321590

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Dataset Information

Unilateral intranigral administration of ?-sitosterol ?-D-glucoside triggers pathological ?-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

Publications

Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

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