Systemic alpha-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F21%3A00550907" target="_blank" >RIV/68378041:_____/21:00550907 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.nature.com/articles/s41380-019-0608-9" target="_blank" >https://www.nature.com/articles/s41380-019-0608-9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41380-019-0608-9" target="_blank" >10.1038/s41380-019-0608-9</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Systemic alpha-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease

Popis výsledku v původním jazyce

Parkinson's disease (PD) is an alpha-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including alpha-synuclein preformed fibrils (pff). We show that a single systemic administration of alpha-synuclein pff triggers pathological transformation of endogenous alpha-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The alpha-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of alpha-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

Název v anglickém jazyce

Systemic alpha-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease

Popis výsledku anglicky

Parkinson's disease (PD) is an alpha-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including alpha-synuclein preformed fibrils (pff). We show that a single systemic administration of alpha-synuclein pff triggers pathological transformation of endogenous alpha-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The alpha-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of alpha-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecular Psychiatry

ISSN

1359-4184

e-ISSN

1476-5578

Svazek periodika

26

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

12

Strana od-do

556-567

Kód UT WoS článku

000613804500017

EID výsledku v databázi Scopus

2-s2.0-85075429616