Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism

Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains, Here we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer's disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain's energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimer's disease risk allele ε4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of zebrafish and of knock-in, single EOfAD mutation models for understanding the causes of this disease.

Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

SummaryEnergy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains. Here, we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer’s disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain’s energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models ofAPOEalleles and found the same effect for the late onset Alzheimer’s disease risk allele ɛ4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer’s disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.

Spinal dysraphism, club feet, and dextrocardia with situs inversus totalis in a neonate: a rare association and review

ObjectivesThe spinal dysraphism and situs inversus are a rare association. Since 1909, reports on the coincidence of malformations of the spine and gastrointestinal tract have been published. So far there is no plausible explanation for the association.Case presentationWe report a term female infant with spinal dysraphism with club feet associated with dextrocardia and situs inversus totalis. Whole genome SNP microarray analysis was normal. However, there are extended contiguous regions of allele homozygosity [>8 Mb[megabase]) observed in chromosome 6 and 14.ConclusionsWe report a rare association of spinal dysraphism and situs inversus totalis in a neonate. We review the literature. There have recently been theorized by some to in fact represent nothing more than the presence of two or more polytopic field defects, with all the anomalies present sharing a common molecular basis.

Methyl-CpG2-binding protein 2 mediates overlapping mechanisms across brain disorders

Methyl-CpG binding protein 2 (MeCP2) is a chromatin-binding protein and a modulator of gene expression. Initially identified as an oncogene, MECP2 is now mostly associated to Rett Syndrome, a neurodevelopmental condition, though there is evidence of its influence in other brain disorders.We design a procedure that considers several binding properties of MeCP2 and we screen for potential targets across neurological and neuropsychiatric conditions.We find MeCP2 target genes associated to a range of disorders, including - among others-Alzheimer Disease, Autism, Attention Deficit Hyperactivity Disorder and Multiple Sclerosis. The analysis of biological mechanisms and pathways modulated by MeCP2’s target genes shows that such mechanisms are involved in three main processes: neuronal transmission, immuno-reactivity and development.These results suggest that similar symptoms present in different pathologies have a common molecular basis, and that treatments for one condition have potential applications to related disorders.

Identifying the causative proteins of similar side effect pairs to explore the common molecular basis of these side effects

Drug side effects, or adverse drug reactions (ADRs), have become a major public health concern and often cause drug development failure and withdrawal.