Maternal Iron Deficiency and Environmental Lead (Pb) Exposure Alter the Predictive Value of Blood Pb Levels on Brain Pb Burden in the Offspring in a Dietary Mouse Model: An Important Consideration for Cumulative Risk in Development.

Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear.

Gestational iron deficiency affects the ratio between interneuron subtypes in the postnatal cerebral cortex in mice.

Gestational iron deficiency (gID) is highly prevalent and associated with an increased risk of intellectual and developmental disabilities in affected individuals that are often defined by a disrupted balance of excitation and inhibition (E/I) in the brain. Using a nutritional mouse model of gID, we previously demonstrated a shift in the E/I balance towards increased inhibition in the brains of gID offspring that was refractory to postnatal iron supplementation. We thus tested whether gID affects embryonic progenitor cells that are fated towards inhibitory interneurons.

Expression of the human herpesvirus 6A latency-associated transcript U94A impairs cytoskeletal functions in human neural cells.

Many neurodegenerative diseases have a multifactorial etiology and variable course of progression that cannot be explained by current models. Neurotropic viruses have long been suggested to play a role in these diseases, although their exact contributions remain unclear. Human herpesvirus 6A (HHV-6A) is one of the most common viruses detected in the adult brain, and has been clinically associated with multiple sclerosis (MS), and, more recently, Alzheimer's disease (AD).

Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection.

Children and young adults with mutant forms of ataxia telangiectasia mutated (ATM), a kinase involved in DNA damage signaling and mitochondrial homeostasis, suffer from recurrent respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. We previously showed in mice how Atm was required to mount a protective immune memory response to influenza A virus [IAV; Hong Kong/X31 (HKx31), H3N2]. Here, Atm wildtype (WT) and knockout (Atm-null) mice were used to investigate how Atm is required to regenerate the injured airway epithelium following IAV infection.

Ataxia-telangiectasia mutated is required for the development of protective immune memory after influenza A virus infection.

Ataxia-telangiectasia (A-T), caused by mutations in the A-T mutated () gene, is a neurodegenerative disorder affecting ∼1 in 40,000-100,000 children. Recurrent respiratory infections are a common and challenging comorbidity, often leading to the development of bronchiectasis in individuals with A-T. The role of ATM in development of immune memory in response to recurrent respiratory viral infections is not well understood.

Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology.

Human herpesviruses (HVs) have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system (CNS). The ability of HVs to enter a state of latency, a defining characteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain.

Iron Deficiency Affects Seizure Susceptibility in a Time- and Sex-Specific Manner.

Iron deficiency (ID) affects more than three billion people worldwide making it the most common micronutrient deficiency. ID is most prevalent during gestation and early life, which is of particular concern since its impact on the developing central nervous system is associated with an increased risk of a wide range of different psychiatric disorders later in life. The cause for this association is not known, but many of these same disorders are also associated with an imbalance between excitation and inhibition (E/I) within the brain.

Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration.

Progression of demyelinating diseases is caused by an imbalance of two opposing processes: persistent destruction of myelin and myelin repair by differentiating oligodendrocyte progenitor cells (OPCs). Repair that cannot keep pace with destruction results in progressive loss of myelin. Viral infections have long been suspected to be involved in these processes but their specific role remains elusive.

Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury.

Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult.

Neuropathological Consequences of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse.

Increasing evidence indicates that the central nervous system (CNS) is a target of air pollution. We previously reported that postnatal exposure of mice to concentrated ambient ultrafine particles (UFP; ≤100 nm) via the University of Rochester HUCAPS system during a critical developmental window of CNS development, equivalent to human 3rd trimester, produced male-predominant neuropathological and behavioral characteristics common to multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), in humans. The current study sought to determine whether vulnerability to fine (≤2.

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity.

Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids.

Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear.

A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden.

Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model.

Identifying the threshold of iron deficiency in the central nervous system of the rat by the auditory brainstem response.

The deleterious effects of anemia on auditory nerve (AN) development have been well investigated; however, we have previously reported that significant functional consequences in the auditory brainstem response (ABR) can also occur as a consequence of marginal iron deficiency (ID). As the ABR has widespread clinical use, we evaluated the ability of this electrophysiological method to characterize the threshold of tissue ID in rats by examining the relationship between markers of tissue ID and severity of ABR latency defects. To generate various levels of ID, female Long-Evans rats were exposed to diets containing sufficient, borderline, or deficient iron (Fe) concentrations throughout gestation and offspring lifetime.

Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.

This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively.

Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice.

Background: Air pollution has been associated with adverse neurological and behavioral health effects in children and adults. Recent studies link air pollutant exposure to adverse neurodevelopmental outcomes, including increased risk for autism, cognitive decline, ischemic stroke, schizophrenia, and depression.

Objectives: We sought to investigate the mechanism(s) by which exposure to ultrafine concentrated ambient particles (CAPs) adversely influences central nervous system (CNS) development.

Gestational iron deficiency differentially alters the structure and function of white and gray matter brain regions of developing rats.

Gestational iron deficiency (ID) has been associated with a wide variety of central nervous system (CNS) impairments in developing offspring. However, a focus on singular regions has impeded an understanding of the CNS-wide effects of this micronutrient deficiency. Because the developing brain requires iron during specific phases of growth in a region-specific manner, we hypothesized that maternal iron deprivation would lead to region-specific impairments in the CNS of offspring.

Oligodendrocyte/type-2 astrocyte progenitor cells and glial-restricted precursor cells generate different tumor phenotypes in response to the identical oncogenes.

Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs), and in astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU.

iOPs: a new tool for studying myelin pathologies?

Generating patient-specific oligodendrocyte progenitors capable of repairing myelination defects observed in multiple neurological afflictions holds great therapeutic potential. Recently in Nature Biotechnology, Najm et al. (2013) and Yang et al.

Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD).

Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide.

Iron deficiency disrupts axon maturation of the developing auditory nerve.

Iron is critical in multiple aspects of CNS development, but its role in neurodevelopment--the ability of iron deficiency to alter normal development--is difficult to dissociate from the effects of anemia. We developed a novel dietary restriction model in the rat that allows us to study the effects of iron deficiency in the absence of severe anemia. Using a combination of auditory brainstem response analyses (ABR) and electron microscopy, we identified an unexpected impact of nonanemic iron deficiency on axonal diameter and neurofilament regulation in the auditory nerve.

Cell therapies for the central nervous system: how do we identify the best candidates?

Purpose Of Review: Central to the obstacles to be overcome in moving promising cell-based therapies from the laboratory to the clinic is that of determining which of the many cell types being examined are optimal for repairing particular lesions.

Recent Findings: Our studies on astrocyte replacement therapies demonstrate clearly that some cells are far better than others at promoting recovery in spinal cord injury and that, at least in some cases, transplanting undifferentiated precursor cells is far less useful than transplanting specific astrocytes derived from those precursor cells. But further comparison between different approaches is hindered by the difficulties in replicating results between laboratories, even for well defined pharmacological agents and bioactive proteins.

Precursor cell biology and the development of astrocyte transplantation therapies: lessons from spinal cord injury.

This review summarizes current progress on development of astrocyte transplantation therapies for repair of the damaged central nervous system. Replacement of neurons in the injured or diseased central nervous system is currently one of the most popular therapeutic goals, but if neuronal replacement is attempted in the absence of appropriate supporting cells (astrocytes and oligodendrocytes), then the chances of restoring neurological functional are greatly reduced. Although the past 20 years have offered great progress on oligodendrocyte replacement therapies, astrocyte transplantation therapies have been both less explored and comparatively less successful.

Oligodendrocyte progenitors reversibly exit the cell cycle and give rise to astrocytes in response to interferon-γ.

Oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs) populate the CNS and generate oligodendrocytes and astrocytes in vitro and in vivo. Understanding how O-2A/OPCs respond to their environment is crucial to understanding how these cells function in the CNS and how to best promote their therapeutic proliferation and differentiation. We show that interferon-γ (IFN-γ) was not toxic to highly purified perinatal or adult rat O-2A/OPCs.

Identifying a window of vulnerability during fetal development in a maternal iron restriction model.

It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses.