Autophagy activation promotes clearance of α-synuclein inclusions in fibril-seeded human neural cells.
J Biol Chem
; 294(39): 14241-14256, 2019 09 27.
Article
em En
| MEDLINE
| ID: mdl-31375560
ABSTRACT
There is much interest in delineating the mechanisms by which the α-synuclein protein accumulates in brains of individuals with Parkinson's disease (PD). Preclinical studies with rodent and primate models have indicated that fibrillar forms of α-synuclein can initiate the propagation of endogenous α-synuclein pathology. However, the underlying mechanisms by which α-synuclein fibrils seed pathology remain unclear. To investigate this further, we have used exogenous fibrillar α-synuclein to seed endogenous α-synuclein pathology in human neuronal cell lines, including primary human neurons differentiated from induced pluripotent stem cells. Fluorescence microscopy and immunoblot analyses were used to monitor levels of α-synuclein and key autophagy/lysosomal proteins over time in the exogenous α-synuclein fibril-treated neurons. We observed that temporal changes in the accumulation of cytoplasmic α-synuclein inclusions were associated with changes in the key autophagy/lysosomal markers. Of note, chloroquine-mediated blockade of autophagy increased accumulation of α-synuclein inclusions, and rapamycin-induced activation of autophagy, or use of 5'-AMP-activated protein kinase (AMPK) agonists, promoted the clearance of fibril-mediated α-synuclein pathology. These results suggest a key role for autophagy in clearing fibrillar α-synuclein pathologies in human neuronal cells. We propose that our findings may help inform the development of human neural cell models for screening of potential therapeutic compounds for PD or for providing insight into the mechanisms of α-synuclein propagation. Our results further add to existing evidence that AMPK activation may be a therapeutic option for managing PD.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Autofagia
/
Corpos de Lewy
/
Alfa-Sinucleína
/
Células-Tronco Neurais
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2019
Tipo de documento:
Article