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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
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La fibronectina celular exacerba la agregación de la α-sinucleína a través de la elevación de la PARP1 y la SCD
Zifeng Huang1, Hui Zhong1, Yingqiong Lu2
1Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, PR China.
Resumen
La fibronectina celular (cFn) agrava la patología de la enfermedad de Parkinson al dañar las mitocondrias y alterar el metabolismo de los lípidos a través de la integrina α4β1, lo que lleva a la agregación de la α-sinucleína. La orientación cFn puede ofrecer un nuevo enfoque terapéutico para la EP.
Área de la Ciencia:
- La neurociencia
- Biología celular
- La bioquímica
Sus antecedentes:
- La disfunción mitocondrial y la desregulación lipídica están implicadas en la patogénesis de la enfermedad de Parkinson (EP).
- No se comprende bien el papel de los componentes de la matriz extracelular, como la fibronectina celular (cFn), en los mecanismos patológicos relacionados con la EP.
Objetivo del estudio:
- Investigar si la fibronectina celular (cFn) contribuye a la anormalidad de la α-sinucleína (α-syn) en la enfermedad de Parkinson (EP).
- Elucidar los mecanismos por los cuales el cFn puede inducir el agotamiento de la energía mitocondrial y interrumpir la homeostasis lipídica.
Principales métodos:
- Se utilizaron modelos de ratón con enfermedad de Parkinson tratados con 1-metil-4-fenil-1,2,3,6-tetrahidropiridina (MPTP) y células neuronales humanas SH-SY5Y.
- Se emplearon modelos de entrega de cFn derivados de astrocitos y modelos de eliminación de cFn mediados por AAV.
- Se evaluó la disfunción mitocondrial mediante microscopía electrónica de transmisión (TEM) y se midieron los niveles de poli (ADP-ribosa) polimerasa-1 (PARP1), α-syn y dismetabolismo lipídico inducido por cFn.
Principales resultados:
- La acumulación excesiva de cFn en la sustancia negra compacta (SNpc) de los ratones tratados con MPTP se correlacionó con la disfunción mitocondrial neuronal exacerbada y la agregación de α-syn.
- cFn activó PARP1 e indujo el agotamiento de NAD+ a través de la integrina α4β1, promoviendo la agregación de α-syn.
- cFn aumentó los ácidos grasos libres y los triglicéridos al unirse a la integrina α4β1, empeorando sinérgicamente la anormalidad α-syn.
- cFn activado por la desaturasa de estearoil-CoA (SCD) a través de la interacción con la integrina α4β1.
- El agotamiento genético de cFn salvó las patologías mitocondriales y α-syn en ratones tratados con MPTP.
Conclusiones:
- La fibronectina celular (cFn) exacerba la agregación de α-syn en la enfermedad de Parkinson a través de la activación mediada por la integrina α4β1 de PARP1 y SCD.
- Estas vías conducen a la disfunción mitocondrial y al dismetabolismo lipídico, contribuyendo a la progresión de la EP.
- La orientación de cFn presenta una estrategia terapéutica potencial para la enfermedad de Parkinson.
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