ABSTRACT
Chromodomain-helicase-DNA-binding protein 8 (CHD8) has been identified as one of the genes with the strongest association with autism. The CHD8 protein is a transcriptional regulator that is expressed in nearly all cell types and has been implicated in multiple cellular processes, including cell cycle, cell adhesion, neuronal development, myelination, and synaptogenesis. Considering the central role of CHD8 in the genetics of autism, a deeper understanding of the physiological functions of CHD8 is important to understand the development of the autism phenotype and potential therapeutic targets. Different CHD8 mutant mouse models were developed to determine autism-like phenotypes and to fully understand their mechanisms. Here, we review the current knowledge on CHD8, with an emphasis on mechanistic lessons gained from animal models that have been studied.
Subject(s)
Autism Spectrum Disorder/physiopathology , DNA-Binding Proteins/physiology , Neurodevelopmental Disorders/physiopathology , Transcription Factors/physiology , Animals , DNA-Binding Proteins/genetics , Disease Models, Animal , Humans , Mice , Phenotype , Transcription Factors/geneticsABSTRACT
The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.
Subject(s)
COVID-19/epidemiology , COVID-19/virology , Disease Susceptibility , Down Syndrome/epidemiology , Adolescent , Adult , Alzheimer Disease/complications , Alzheimer Disease/epidemiology , Alzheimer Disease/immunology , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Comorbidity , Disease Susceptibility/immunology , Disease Susceptibility/virology , Down Syndrome/complications , Down Syndrome/immunology , Female , Hospitalization , Humans , Immune System/abnormalities , Incidence , Male , Pandemics/prevention & control , Prevalence , Risk Factors , Vaccination/methodsABSTRACT
Graft-versus-host disease (GVHD) and transplant rejection as a result of host-versus-graft (HVG) response have remained two major complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). When donors are partially HLA-mismatched unrelated or haploidentical related, their severity correlates with the degree of HLA disparity. Specific elimination of alloreactive donor or recipient T cells targeting the mismatched HLA products could markedly alleviate both complications while only minimally affecting graft-versus-tumor (GVT) response or engraftment. To redirect human CD8 T cells against alloreactive CD8 T cells we electroporate these cells with in-vitro-transcribed mRNA encoding MHC-I heavy chains fused with the signaling portion of CD3ζ. Here we show that peripheral blood human CD8 T cells expressing H-2Kb/CD3ζ or H-2Kd/CD3ζ respond to anti-MHC-I stimuli in a strictly specific manner. This study paves the way for further advancing this approach as a means to dampen GVHD and HVG that are caused by HLA disparity in allo-HSCT.
