APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder

Metabolites of the Amyloid-β precursor protein (APP) proteolysis may underlie brain overgrowth in Autism Spectrum Disorder (ASD). We have found elevated APP metabolites (total APP, secreted (s) APPα, and α-secretase adamalysins in the plasma and brain tissue of children with ASD). In this review, we highlight several lines of evidence supporting APP metabolites’ potential contribution to macrocephaly in ASD. First, APP appears early in corticogenesis, placing APP in a prime position to accelerate growth in neurons and glia. APP metabolites are upregulated in neuroinflammation, another potential contributor to excessive brain growth in ASD. APP metabolites appear to directly affect translational signaling pathways, which have been linked to single gene forms of syndromic ASD (Fragile X Syndrome, PTEN, Tuberous Sclerosis Complex). Finally, APP metabolites, and microRNA, which regulates APP expression, may contribute to ASD brain overgrowth, particularly increased white matter, through ERK receptor activation on the PI3K/Akt/mTOR/Rho GTPase pathway, favoring myelination

Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)

The goal of genome-wide association studies is to identify SNPs unique to disease. It usually involves a single sampling from subjects' lifetimes. While primary DNA sequence variation influences gene-expression levels, expression is also influenced by epigenetics, including the ‘somatic epitype’ (GSE), an epigenotype acquired postnatally. While genes are inherited, and novel polymorphisms do not routinely appear, GSE is fluid. Furthermore, GSE could respond to environmental factors (such as heavy metals) and to differences in exercise, maternal care and dietary supplements – all of which postnatally modify oxidation or methylation of DNA, leading to altered gene expression. Change in epigenetic status may be critical for the development of many diseases. We propose a ‘longitudinal epigenome-wide association study’, wherein GSE are measured at multiple time points along with subjects' histories. This Longitudinal epigenome-wide association study, based on the ‘dynamic’ somatic epitype over the ‘static’ genotype, merits further investigation

Neurodevelopmental disorders and microcephaly: how apoptosis, the cell cycle, tau and amyloid-β precursor protein APPly

Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer’s Disease. We have reported high levels of Amyloid-β Precursor Protein (APP) and secreted APP-alpha (sAPPa) and low levels of amyloid-beta (Aβ) peptides 1–40 and 1–42 (Aβ40, Aβ42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3rd percentile) associates with ASD compared to head size in individuals with typical development. The role of Aβ peptides as contributors to acquired microcephaly in ASD is proposed. Aβ may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aβ peptides occur in Trisomy 21-T21 (Down’s Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aβ peptides’ role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome

Glucocorticoid-Induced Leucine Zipper in Central Nervous System Health and Disease

The central nervous system (CNS) is a large network of intercommunicating cells that function to maintain tissue health and homeostasis. Considerable evidence suggests that glucocorticoids exert both neuroprotective and neurodegenerative effects on the CNS. Glucocorticoids act by binding two related receptors in the cytoplasm, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The glucocorticoid receptor complex mediates cellular responses by transactivating target genes and by protein: protein interactions. The paradoxical effects of glucocorticoids on neuronal survival and death have been attributed to the concentration and the ratio of mineralocorticoid to glucocorticoid receptor activation. Glucocorticoid-induced leucine zipper (GILZ) is a recently identified protein transcriptionally upregulated by glucocorticoids. Constitutively, expressed in many tissues including brain, GILZ mediates many of the actions of glucocorticoids. It mimics the anti-inflammatory and anti-proliferative effects of glucocorticoids but exerts differential effects on stem cell differentiation and lineage development. Recent experimental data on the effects of GILZ following induced stress or trauma suggest potential roles in CNS diseases. Here, we provide a short overview of the role of GILZ in CNS health and discuss three potential rationales for the role of GILZ in Alzheimer’s disease pathogenesis

Significance of NF-κΒ as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis

Introduction: Advances in molecular pathogenesis suggest that the chronic inflammation is a shared mechanism in the initiation and progression of multiple neurodegenerative diseases with diverse clinical manifestations such as Alzheimer’s disease (AD) and Multiple sclerosis (MS). Restricted cell renewal and regenerative capacity make the neural tissues extremely vulnerable to the uncontrolled inflammatory process leading to irreversible tissue damage. Areas covered: A predominant consequence of increased inflammatory signaling is the upregulation of the transcription factor, NF-κB with subsequent neuroprotective or deleterious effects depending on the strength of the signal and the type of NF-κB dimers activated. We discuss the interplay between neuroinflammation and neurodegeneration keeping in focus NF-κB signaling as the point of convergence of multiple pathways associated with the development of the neurodegenerative pathologies, AD and MS. Expert opinion: Considerable interest exists in developing efficient NF-κB inhibitors for neurodegenerative diseases. The review includes an overview of natural compounds and rationally designed agents that inhibit NF-κB and mediate neuroprotection in AD and MS. The key chemical moieties of the natural and the synthetic compounds provide efficient leads for the development of effective small molecule inhibitors that selectively target NF-κB activation; this would result in the desired benefit to risk therapeutic effects

The Genetics of Autism

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.This chapter is written to make the fast-paced, expanding field of the genetics of autism accessible to those practitioners who help children with autism. New genetic knowledge and technology have quickly developed over the past 30 years, particularly within the past decade, and have made many optimistic about our ability to explain autism. Among these advances include the sequencing of the human genome (Lander et al., 2001) and the identification of common genetic variants via the HapMap project (International HapMap Consortium, 2005), and the development of cost-efficient genotyping and analysis technologies (Losh, Sullivan, Trembath, & Piven, 2008). Improvement in technology has led to improved visualization of chromosomal abnormality down to the molecular level. The four most common syndromes associated with autism include fragile X syndrome, tuberous sclerosis, 15q duplications, and untreated phenylketonuria (PKU; Costa e Silva, 2008). FXS and 15q duplications are discussed within the context of cytogenetics. TSC is illustrated within the description of linkage analysis

Preclinical characterization of drug like glucocorticoid induced leucine zipper peptide analogs

poster abstractMany intermolecular interactions in a eukaryotic cell are mediated through protein-peptide interactions. For efficient interaction, the peptide scans the protein surface for a large enough pocket into which it anchors through a small number of residues/core motif that contribute maximally to the free energy of binding. Of special significance is the preponderance of proline rich sequences that preferentially adopt the left-handed polyproline type II (PPII) helical conformation in the interface peptides. Availability of both side chain and backbone carbonyls for interaction makes PPII helix an excellent recognition motif. Glucocorticoid induced leucine zipper (GILZ), is a glucocorticoid responsive protein that has been shown to suppress immuno-inflammatory responses by preventing the nuclear translocation of the p65 subunit of the transcription factor nuclear factor-kappa B (NF-κB). Mutational and binding studies localized the sites of interaction to the proline rich region at the carboxy terminus of GILZ and the transactivation domain of p65. Similar to most intermolecular interactions mediated by proline rich motifs the strength of interaction between the GILZ and the p65 proteins is in the micromolar concentration suggesting weak binding kinetics. A widely used strategy in the discovery of peptide drugs involves exploitation of the complementary surfaces of the naturally occurring binding partners. We observed that a synthetic peptide (GILZ-P) derived from the proline rich region of GILZ suppressed immune mediated inflammatory responses in mice. Here we characterize GILZ-P structurally and evaluate its toxicity and efficacy in mature human macrophage like THP-1 cells. We show that the GILZ-P adopts an extended polyproline type II helical conformation. Functionally GILZ-P is non-toxic, suppresses NF B activation on by activated macrophages suggesting a therapeutic potential in pathologies wherein persistent inflammation plays critical role in the disease initiation and/or progression

When figures and data contradict text: MiR346 is apparently reduced in breast cancer tissue, contrary to claims by a paper's author

A recent article in Gene highlighted potential function of miR-346 in human breast cancer (Yang et al., 2017). We request an explanation or correction of the report. In its current state, the text will certainly create confusion in the field and lead to incorrect assumptions. The authors made several critical errors. The abstract stated “we found that the expression of miR-346 was higher in breast cancer tissues than in their paired corresponding non-cancerous tissues” and the main text and legend for Fig. 1A stated “miR-346 expression was significantly higher in breast cancer tissues than in their paired corresponding non-cancerous tissues (Fig. 1A, Yang et al., 2017)” and “miR-346 was upregulated in breast cancer tissues and cell lines. (A)”, respectively. It was also stated that “SRCIN1 expression levels were significantly down-regulated in breast cancer compared to the adjacent normal tissues (Fig. 5B, Yang et al., 2017)”. The problem with these statements is that they contradict the actual data presented in the paper! This misrepresentation of the effects of miR-346 in breast cancer could prove harmful by sidetracking future research. Further, clinical trials may be incorrectly directed towards lowering miR-346 without a complete and fair assessment of the internal contradictions in the data. Inaccurately-presented data impede progress of biomedical research, deplete scientific resources and compromise public trust