RESUMEN
Stress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a high-content screen to identify small molecules that alter SG properties in proliferative cells and human iPSC-derived motor neurons (iPS-MNs). One major class of active molecules contained extended planar aromatic moieties, suggesting a potential to intercalate in nucleic acids. Accordingly, we show that several hit compounds can prevent the RNA-dependent recruitment of the ALS-associated RNA-binding proteins (RBPs) TDP-43, FUS, and HNRNPA2B1 into SGs. We further demonstrate that transient SG formation contributes to persistent accumulation of TDP-43 into cytoplasmic puncta and that our hit compounds can reduce this accumulation in iPS-MNs from ALS patients. We propose that compounds with planar moieties represent a promising starting point to develop small-molecule therapeutics for treating ALS/FTD.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Gránulos Citoplasmáticos/efectos de los fármacos , Proteínas de Unión al ADN/efectos de los fármacos , Demencia Frontotemporal/metabolismo , Neuronas Motoras/efectos de los fármacos , Agregación Patológica de Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Estrés Fisiológico/efectos de los fármacos , Línea Celular , Gránulos Citoplasmáticos/metabolismo , ADN Helicasas/genética , Proteínas de Unión al ADN/metabolismo , Células HEK293 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Células Madre Pluripotentes Inducidas , Proteínas Intrínsecamente Desordenadas , Neuronas Motoras/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , ARN Helicasas/genética , Proteínas con Motivos de Reconocimiento de ARN/genética , Proteína FUS de Unión a ARN/metabolismoRESUMEN
Globalization and urbanization in Nepal have driven a nutritional transition from an agricultural-based diet to an ultra-processed, sugary diet. This study assessed the nutrition and oral health of 836 children age 6 months to 6 years and their families in rural and urban Nepal. Mothers were interviewed about maternal-child oral health and nutrition, and children received dental exams and height and weight measurements. Analyses utilized SPSS statistical software. Most families lived within a 5-minute walk to a store selling ultra-processed snacks and sugary drinks. While most mothers knew sweets caused tooth decay, half of the children were given sweets daily, and 58.2% of children had dental caries. Caries began in the first 2 years and increased in prevalence and severity to age 6, when 74.3% had caries and 20% experienced mouth pain. Despite greater health knowledge and resources among urban mothers, urban children's increased access to junk food and frequency of consumption was associated with higher prevalence and severity of caries compared to rural children. Severe caries was associated with malnutrition, especially in rural children. Preventive strategies are needed in early childhood to incorporate nutrition and oral health education and dental care into maternal-child health services, and develop policies to prohibit the sale of junk food around schools.
