TY - JOUR
T1 - Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat
AU - Soto-Rojas, Luis O.
AU - Martínez-Dávila, Irma A.
AU - Luna-Herrera, Claudia
AU - Gutierrez-Castillo, María E.
AU - Lopez-Salas, Francisco E.
AU - Gatica-Garcia, Bismark
AU - Soto-Rodriguez, Guadalupe
AU - Bringas Tobon, María Elena
AU - Flores, Gonzalo
AU - Padilla-Viveros, America
AU - Bañuelos, Cecilia
AU - Blanco-Alvarez, Víctor Manuel
AU - Dávila-Ayala, José
AU - Reyes-Corona, David
AU - Garcés-Ramírez, Linda
AU - Hidalgo-Alegria, Oriana
AU - De La Cruz-López, Fidel
AU - Martinez-Fong, Daniel
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/4/22
Y1 - 2020/4/22
N2 - 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.
AB - 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.
KW - BSSG
KW - Bilateral affectation
KW - Lewy body-like synuclein aggregations
KW - Parkinson's disease
KW - Sensorimotor alterations
KW - Synuclein spreading
UR - http://www.scopus.com/inward/record.url?scp=85083948811&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-00933-6
DO - 10.1186/s40478-020-00933-6
M3 - Artículo
C2 - 32321590
SN - 2051-5960
VL - 8
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 56
ER -