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Artículo

New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment

Maniscalchi Velásquez, Athina del Valle; Benzi Juncos, Oriana NicoleIcon ; Conde, Melisa AilénIcon ; Funk, Melania IaraIcon ; Fermento, María EugeniaIcon ; Facchinetti, Maria MartaIcon ; Curino, Alejandro CarlosIcon ; Uranga, Romina MariaIcon ; Alza, Natalia PaolaIcon ; Salvador, Gabriela AlejandraIcon
Fecha de publicación: 05/02/2024
Editorial: Elsevier
Revista: Redox Biology
ISSN: 2213-2317
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metal accumulation associated with dopaminergic neuronal death has been documented in Parkinson's disease. Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronal and glial response during iron overload. In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated in mice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevated expression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in the midbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymes was identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl ester levels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice. In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into the mechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation. We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found that the ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes. Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as a consequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest that developing therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegeneration associated with ferroptosis and brain iron accumulation.
Palabras clave: Iron accumulation , Midbrain neurodegeneration , Lipid cacostasis , Cholesterol accumulation , Ferroptosis , Movement disorders
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/230898
DOI: http://dx.doi.org/10.1016/j.redox.2024.103074
URL: https://www.sciencedirect.com/science/article/pii/S2213231724000508
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Articulos(INIBIBB)
Articulos de INST.DE INVEST.BIOQUIMICAS BAHIA BLANCA (I)
Citación
Maniscalchi Velásquez, Athina del Valle; Benzi Juncos, Oriana Nicole; Conde, Melisa Ailén; Funk, Melania Iara; Fermento, María Eugenia; et al.; New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment; Elsevier; Redox Biology; 71; 103074; 5-2-2024; 1-18
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