RESUMEN
Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
Asunto(s)
Envejecimiento/genética , Proteína 7 Relacionada con la Autofagia/genética , Disfunción Cognitiva/genética , Suplementos Dietéticos , Proteínas Quinasas/genética , Espermidina/farmacología , Ubiquitina-Proteína Ligasas/genética , Envejecimiento/metabolismo , Animales , Proteína 7 Relacionada con la Autofagia/metabolismo , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/prevención & control , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Proteínas Quinasas/metabolismo , Transducción de Señal , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a human FAD-dependent enzyme that plays a crucial role in the antioxidant defense system. A naturally occurring single-nucleotide polymorphism (NQO1*2) in the NQO1 gene leads to an amino acid substitution (P187S), which severely compromises the activity and stability of the enzyme. The NQO1*2 genotype has been linked to a higher risk for several types of cancer and poor survival rate after anthracycline-based chemotherapy. In this study, we show that a small molecular chaperone (N-(2-bromophenyl)pyrrolidine-1-sulfonamide) repopulates the native wild-type conformation. As a consequence of the stabilizing effect, the enzymatic activity of the P187S variant protein is strongly improved in the presence of the molecular chaperone in vitro.
Asunto(s)
Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Neoplasias/genética , Secuencia de Aminoácidos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Estabilidad de Enzimas/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/química , NAD(P)H Deshidrogenasa (Quinona)/antagonistas & inhibidores , NAD(P)H Deshidrogenasa (Quinona)/química , Conformación ProteicaRESUMEN
Cytoplasmic FUS aggregates are a pathological hallmark in a subset of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). A key step that is disrupted in these patients is nuclear import of FUS mediated by the import receptor Transportin/Karyopherin-ß2. In ALS-FUS patients, this is caused by mutations in the nuclear localization signal (NLS) of FUS that weaken Transportin binding. In FTD-FUS patients, Transportin is aggregated, and post-translational arginine methylation, which regulates the FUS-Transportin interaction, is lost. Here, we show that Transportin and arginine methylation have a crucial function beyond nuclear import-namely to suppress RGG/RG-driven phase separation and stress granule association of FUS. ALS-associated FUS-NLS mutations weaken the chaperone activity of Transportin and loss of FUS arginine methylation, as seen in FTD-FUS, promote phase separation, and stress granule partitioning of FUS. Our findings reveal two regulatory mechanisms of liquid-phase homeostasis that are disrupted in FUS-associated neurodegeneration.