Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Stem Cell Res ; 71: 103134, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37336145

RESUMEN

Mutations or multiplications of the SNCA (Synuclein Alpha) gene cause rare autosomal dominant Parkinson's disease (PD). The SNCA G51D missense mutation is associated with a synucleinopathy that shares PD and multiple system atrophy (MSA) characteristics. We generated induced pluripotent stem cell (iPSC) lines from two individuals with SNCA G51D missense mutations at risk of PD. Dermal fibroblasts were reprogrammed to pluripotency using a non-integrating mRNA-based protocol. The resulting human iPSCs displayed normal morphology, expressed markers associated with pluripotency, and differentiated into the three germ layers. The iPSC lines could facilitate disease-modelling and therapy development studies for synucleinopathies.


Asunto(s)
Células Madre Pluripotentes Inducidas , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Mutación Missense , Células Madre Pluripotentes Inducidas/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/metabolismo , Mutación
3.
Nat Neurosci ; 25(9): 1134-1148, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36042314

RESUMEN

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.


Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Cardiolipinas/metabolismo , Humanos , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...