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1.
Nature ; 575(7781): 203-209, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31666698

RESUMEN

Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)1 and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington's disease, an incurable neurodegenerative disorder2. Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington's disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract3. This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.


Asunto(s)
Alelos , Evaluación Preclínica de Medicamentos/métodos , Proteína Huntingtina/antagonistas & inhibidores , Proteína Huntingtina/genética , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/genética , Mutación/genética , Animales , Ataxina-3/genética , Autofagosomas/metabolismo , Autofagia , Modelos Animales de Enfermedad , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Femenino , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/metabolismo , Masculino , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutación/efectos de los fármacos , Neuronas/citología , Péptidos/genética , Fenotipo , Reproducibilidad de los Resultados
2.
Cell ; 129(2): 371-83, 2007 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-17448995

RESUMEN

Sodium plays a key role in determining the basal excitability of the nervous systems through the resting "leak" Na(+) permeabilities, but the molecular identities of the TTX- and Cs(+)-resistant Na(+) leak conductance are totally unknown. Here we show that this conductance is formed by the protein NALCN, a substantially uncharacterized member of the sodium/calcium channel family. Unlike any of the other 20 family members, NALCN forms a voltage-independent, nonselective cation channel. NALCN mutant mice have a severely disrupted respiratory rhythm and die within 24 hours of birth. Brain stem-spinal cord recordings reveal reduced neuronal firing. The TTX- and Cs(+)-resistant background Na(+) leak current is absent in the mutant hippocampal neurons. The resting membrane potentials of the mutant neurons are relatively insensitive to changes in extracellular Na(+) concentration. Thus, NALCN, a nonselective cation channel, forms the background Na(+) leak conductance and controls neuronal excitability.


Asunto(s)
Canales Iónicos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Respiración , Sodio/metabolismo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Calcio/metabolismo , Línea Celular , Sistema Nervioso Central/citología , Cesio/farmacología , ADN Complementario , Embrión de Mamíferos/metabolismo , Embrión no Mamífero , Genes Letales , Hipocampo/citología , Humanos , Canales Iónicos/química , Canales Iónicos/genética , Potenciales de la Membrana , Proteínas de la Membrana , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Potasio/metabolismo , Ratas , Alineación de Secuencia , Tetrodotoxina/farmacología , Transfección , Xenopus
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