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 CebraRESUMEN
Using an ethnomedical data approach, some Georgian plants, which are used in Georgian traditional medicine for cancer or non-cancer diseases, were collected and evaluated for cytotoxic activity. The cytotoxic effect of the methanol extracts of species from the genera Galanthus and Leucojum was evaluated in vitro on three human cell lines (Hela, ephitheloid cervix carcinoma; HCT-116, colon carcinoma; HL-60, acute myeloid leukaemia). Cell type cytotoxic specificity was observed for some extracts. Overall, the HCT-116 cells were much more sensitive to most of the extracts than were the other cell lines. Plants that showed pronounced cytotoxic activity will be further evaluated for the possible isolation of active antitumour compounds.