RESUMEN

Alzheimer's disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer's disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches.

Asunto(s)

Proteínas de Caenorhabditis elegans , Enfermedades Neurodegenerativas , Tauopatías , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Modelos Animales de Enfermedad , Humanos , Tauopatías/genética

RESUMEN

Family health history (FHH) screening plays a key role in disease risk identification and tailored disease prevention strategies. Primary care physicians (PCPs) are in a frontline position to provide personalized medicine recommendations identified through FHH screening; however, adoption of FHH screening tools has been slow and inconsistent in practice. Information is also lacking on PCP facilitators and barriers of utilizing family history tools with clinical decision support (CDS) embedded in the electronic health record (EHR). This study reports on PCPs' initial experiences with the Genetic and Wellness Assessment (GWA), a patient-administered FHH screening tool utilizing the EHR and CDS. Semi-structured interviews were conducted with 24 PCPs who use the GWA in a network of community-based practices. Four main themes regarding GWA implementation emerged: benefits to clinical care, challenges in practice, CDS-specific issues, and physician-recommended improvements. Sub-themes included value in improving patient access to genetic services, inadequate time to discuss GWA recommendations, lack of patient follow-through with recommendations, and alert fatigue. While PCPs valued the GWA's clinical utility, a number of challenges were identified in the administration and use of the GWA in practice. Based on participants' recommendations, iterative changes have been made to the GWA and workflow to increase efficiency, upgrade the CDS process, and provide additional education to PCPs and patients. Future studies are needed to assess a diverse sample of physicians' and patients' perspectives on the utility of FHH screening utilizing EHR-based genomics recommendations.