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1.
CNS Neurosci Ther ; 30(2): e14600, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38357857

RESUMEN

AIM: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). METHODS: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. RESULTS: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. CONCLUSIONS: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.


Asunto(s)
Factor 15 de Diferenciación de Crecimiento , Leucoencefalopatías , Humanos , Ratones , Animales , Factor 15 de Diferenciación de Crecimiento/genética , Leucoencefalopatías/genética , Sistema Nervioso Central/metabolismo , Factor 2B Eucariótico de Iniciación/genética , Factor 2B Eucariótico de Iniciación/metabolismo , Biomarcadores
2.
J Neurochem ; 134(2): 261-75, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25807858

RESUMEN

A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion.


Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Regeneración Nerviosa/fisiología , Neuronas/patología , Traumatismos de la Médula Espinal/patología , Factores de Transcripción/biosíntesis , Quinasas Asociadas a rho/biosíntesis , Animales , Axones , Secuencia de Bases , Western Blotting , Supervivencia Celular , Proteínas de Unión al ADN/genética , Dependovirus , Modelos Animales de Enfermedad , Femenino , Terapia Genética/métodos , Vectores Genéticos , Inmunohistoquímica , Datos de Secuencia Molecular , ARN Interferente Pequeño , Ratas , Ratas Wistar , Recuperación de la Función , Núcleo Rojo/patología , Factores de Transcripción/genética , Quinasas Asociadas a rho/genética
3.
Brain Pathol ; 25(2): 157-70, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25040536

RESUMEN

Axonal degeneration is one of the initial steps in many neurological disorders and has been associated with increased autophagic activity. Although there are increasing data on the regulation of autophagy proteins in the neuronal soma after spinal cord injury (SCI), their characterization in the axon is scarce. Here, we examined the regulation of autophagy during axonal degeneration in a rat model of SCI following a lesion at Th 8. We analyzed the morphological and ultrastructural changes in injured axons by immunohistochemical evaluation of autophagy-related proteins and electron microscopy at different time points following SCI. The expression of ULK1, Atg7 and Atg5 in damaged axons was rapidly upregulated within hours after SCI. The number of axonal LC3-positive autophagosomes was also rapidly increased after SCI and remained at an increased level for up to 6 weeks. Ultrastructural analysis showed early signs of axonal degeneration and increased autophagy. In conclusion, we show that autophagy is increased early and for a sustained period in degenerating axons after SCI and that it might be an important executive step involved in axonal degeneration. Therefore, autophagy may represent a promising target for future therapeutic interventions in the treatment of axonal degeneration in traumatic central nervous system disorders.


Asunto(s)
Autofagia , Axones/metabolismo , Degeneración Nerviosa/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Proteína 5 Relacionada con la Autofagia , Proteína 7 Relacionada con la Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia , Axones/ultraestructura , Femenino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas/metabolismo , Ratas , Ratas Wistar , Traumatismos de la Médula Espinal/patología , Enzimas Activadoras de Ubiquitina/metabolismo , Regulación hacia Arriba
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