RESUMO
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.
Assuntos
Alelos , Avaliação Pré-Clínica de Medicamentos/métodos , Proteína Huntingtina/antagonistas & inibidores , Proteína Huntingtina/genética , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/genética , Mutação/genética , Animais , Ataxina-3/genética , Autofagossomos/metabolismo , Autofagia , Modelos Animais de Doenças , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Feminino , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/metabolismo , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação/efeitos dos fármacos , Neurônios/citologia , Peptídeos/genética , Fenótipo , Reprodutibilidade dos TestesRESUMO
Superlubricity between a cone-shaped (sharp) silicon tip and graphite remains a challenge in the nanotribology field. In this paper, an efficient method of achieving superlubricity between a cone-shaped silicon tip and graphite was proposed. Graphite nanoflakes were transferred onto the silicon tip by repeatedly rubbing against the scratches produced by nanolithography on a graphite surface. The superlubricity between the graphite nanoflakes-wrapped tip and highly oriented pyrolytic graphite (HOPG) was attained, and the friction coefficient was reduced to 0.0007. At low normal loads, the frictional force was small and showed a strong correlation with the sliding angle, but as the normal load increased, this dependence gradually decreased. It was firstly found that the transferred graphite nanoflakes on the contact zone of the silicon tip could be transformed into amorphous carbon layers induced by the shear force and high pressure during the superlubricity test process.