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1.
Hum Mol Genet ; 27(7): 1276-1289, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29415125

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration.


Asunto(s)
Esclerosis Amiotrófica Lateral , Histona Acetiltransferasas , Corteza Motora/metabolismo , Proteínas del Tejido Nervioso , ARN de Transferencia , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Procesamiento Postranscripcional del ARN , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Pez Cebra
2.
Hum Mol Genet ; 22(9): 1783-90, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23364049

RESUMEN

Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because α-tubulin acetylation facilitates axonal transport, inhibition of the α-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1(G93A) mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1(G93A) mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased α-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify α-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major α-tubulin deacetylase in the nervous system.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Eliminación de Gen , Histona Desacetilasas/genética , Sirtuina 2/genética , Acetilación , Esclerosis Amiotrófica Lateral/patología , Animales , Transporte Axonal/genética , Axones/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Histona Desacetilasa 6 , Histona Desacetilasas/metabolismo , Masculino , Ratones , Ratones Transgénicos , Sirtuina 2/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Tubulina (Proteína)/metabolismo
3.
Neuron ; 72(5): 776-88, 2011 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-22153374

RESUMEN

Elongator protein 3 (ELP3) acetylates histones in the nucleus but also plays a role in the cytoplasm. Here, we report that in Drosophila neurons, ELP3 is necessary and sufficient to acetylate the ELKS family member Bruchpilot, an integral component of the presynaptic density where neurotransmitters are released. We find that in elp3 mutants, presynaptic densities assemble normally, but they show morphological defects such that their cytoplasmic extensions cover a larger area, resulting in increased vesicle tethering as well as a more proficient neurotransmitter release. We propose a model where ELP3-dependent acetylation of Bruchpilot at synapses regulates the structure of individual presynaptic densities and neurotransmitter release efficiency.


Asunto(s)
Acetiltransferasas , Proteínas de Drosophila/metabolismo , Histona Acetiltransferasas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Unión Neuromuscular/metabolismo , Terminales Presinápticos/fisiología , Acetilación , Animales , Animales Modificados Genéticamente , Línea Celular Transformada , Drosophila , Proteínas de Drosophila/genética , Embrión de Mamíferos , Proteínas Fluorescentes Verdes/genética , Histona Acetiltransferasas/genética , Humanos , Larva , Microscopía Electrónica de Transmisión , Mutación/genética , Proteínas del Tejido Nervioso/genética , Unión Neuromuscular/fisiología , Técnicas de Placa-Clamp , Terminales Presinápticos/ultraestructura , Transfección/métodos , Tubulina (Proteína)/metabolismo , Pez Cebra
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