RESUMEN
PTEN-induced kinase 1 (PINK1) is a serine/threonine kinase that is localized to mitochondria. It protects cells from oxidative stress by suppressing mitochondrial cytochrome c release, thereby preventing cell death. Mutations in Pink1 cause early-onset Parkinson's disease (PD). Consistently, mitochondrial function is impaired in Pink1-linked PD patients and model systems. Previously, in vitro analysis implied that the protective effects of PINK1 depend on phosphorylation of the downstream factor, TNF receptor-associated protein 1 (TRAP1). Furthermore, TRAP1 has been shown to mitigate α-Synuclein-induced toxicity, linking α-Synuclein directly to mitochondrial dysfunction. These data suggest that TRAP1 seems to mediate protective effects on mitochondrial function in pathways that are affected in PD. Here we investigated the potential of TRAP1 to rescue dysfunction induced by either PINK1 or Parkin deficiency in vivo and in vitro. We show that overexpression of human TRAP1 is able to mitigate Pink1 but not parkin loss-of-function phenotypes in Drosophila. In addition, detrimental effects observed after RNAi-mediated silencing of complex I subunits were rescued by TRAP1 in Drosophila. Moreover, TRAP1 was able to rescue mitochondrial fragmentation and dysfunction upon siRNA-induced silencing of Pink1 but not parkin in human neuronal SH-SY5Y cells. Thus, our data suggest a functional role of TRAP1 in maintaining mitochondrial integrity downstream of PINK1 and complex I deficits but parallel to or upstream of Parkin.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Animales Modificados Genéticamente , Línea Celular , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimología , Drosophila melanogaster/genética , Femenino , Técnicas de Inactivación de Genes , Proteínas HSP90 de Choque Térmico/genética , Humanos , Masculino , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Initial sporadic experiences in a Berlin nursing home showed that residents with dementia responded well to activating therapy with tablet computers. This innovative technology seemed to provide a differentiated and individual therapeutic access. These observations encouraged the nursing home management to contact the Institute of Medical Sociology and Rehabilitation Science at the Charité Universitätsmedizin Berlin with the aim to examine the practical experiences. The Centre for Quality in Care (ZQP) sponsored the 1 year pilot study. OBJECTIVE: An examination of the feasibility and usability of tablet computers in the daily care of nursing home residents with dementia was carried out. MATERIALS AND METHODS: In this study 14 residents (12 women and 2 men) of a special care unit for dementia patients were included in a 3-month intervention of tablet activation 3 times a week. Qualitative and quantitative methods were used to analyze data (e.g. observation protocols and videos, staff interviews, document analysis of nursing records and standardized resident interviews/proxy interviews). RESULTS: Nursing home residents suffering from dementia showed a high degree of acceptance of tablet computers. Most notable benefits were easy handling and the variety of multifunctional applications. Sustainable therapeutic effects resulted in stimulation of communication and interaction, improvement of well-being, memory training and reduction of neuropsychiatric symptoms. Furthermore, contact to family members of several residents was improved. CONCLUSIONS: The use of tablet computers was convincing as an activation therapy for nursing home residents with dementia. Further research and development of specially adapted software are required.
Asunto(s)
Equipos de Comunicación para Personas con Discapacidad , Computadoras de Mano , Demencia/rehabilitación , Hogares para Ancianos , Casas de Salud , Aceptación de la Atención de Salud , Anciano , Anciano de 80 o más Años , Demencia/diagnóstico , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Terapia Ocupacional/métodos , Proyectos Piloto , Conducta Social , Terapia Asistida por Computador/métodos , Resultado del TratamientoRESUMEN
Polyglutamine (polyQ) diseases represent a neuropathologically heterogeneous group of disorders. The common theme of these disorders is an elongated polyQ tract in otherwise unrelated proteins. So far, only symptomatic treatment can be applied to patients suffering from polyQ diseases. Despite extensive research, the molecular mechanisms underlying polyQ-induced toxicity are largely unknown. To gain insight into polyQ pathology, we performed a large-scale RNAi screen in Drosophila to identify modifiers of toxicity induced by expression of truncated Ataxin-3 containing a disease-causing polyQ expansion. We identified various unknown modifiers of polyQ toxicity. Large-scale analysis indicated a dissociation of polyQ aggregation and toxicity.