Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder.

CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene.

A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility.

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.

Redox and Calcium Alterations of a Müller Cell Line Exposed to Diabetic Retinopathy-Like Environment.

Diabetic retinopathy (DR) is a common complication of diabetes mellitus and is the major cause of vision loss in the working-age population. Although DR is traditionally considered a microvascular disease, an increasing body of evidence suggests that neurodegeneration is an early event that occurs even before the manifestation of vasculopathy. Accordingly, attention should be devoted to the complex neurodegenerative process occurring in the diabetic retina, also considering possible functional alterations in non-neuronal cells, such as glial cells.

Amiodarone in ventricular arrhythmias: still a valuable resource?

Ventricular arrhythmias still represent an important cause of morbidity and mortality, especially in patients with heart failure and reduced left ventricular ejection fraction. Amiodarone is a Class III Vaughan-Williams anti-arrhythmic drug widely used in ventricular arrhythmias for its efficacy and low pro-arrhythmogenic effect. On the other hand, a significant limitation in its use is represented by toxicity.

Gα13 Contributes to LPS-Induced Morphological Alterations and Affects Migration of Microglia.

Microglia are the resident immune cells of the CNS that are activated in response to a variety of stimuli. This phenotypical change is aimed to maintain the local homeostasis, also by containing the insults and repair the damages. All these processes are tightly regulated and coordinated and a failure in restoring homeostasis by microglia can result in the development of neuroinflammation that can facilitate the progression of pathological conditions.

Upregulation of Peroxiredoxin 3 Protects 2-KO Cortical Neurons from Oxidative Stress: A Paradigm for Neuronal Cell Survival under Neurodegenerative Conditions.

Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from -KO mice.

Interaction with hyaluronan matrix and miRNA cargo as contributors for in vitro potential of mesenchymal stem cell-derived extracellular vesicles in a model of human osteoarthritic synoviocytes.

Background: Osteoarthritis (OA) is the most prevalent joint disease, and to date, no options for effective tissue repair and restoration are available. With the aim of developing new therapies, the impact of mesenchymal stem cells (MSCs) has been explored, and the efficacy of MSCs started to be deciphered. A strong paracrine capacity relying on both secreted and vesicle-embedded (EVs) protein or nucleic acid-based factors has been proposed as the principal mechanism that contributes to tissue repair.

eIF4B phosphorylation at Ser504 links synaptic activity with protein translation in physiology and pathology.

Neuronal physiology requires activity-driven protein translation, a process in which translation initiation factors are key players. We focus on eukaryotic initiation factor 4B (eIF4B), a regulator of protein translation, whose function in neurons is undetermined. We show that neuronal activity affects eIF4B phosphorylation and identify Ser504 as a phosphorylation site regulated by casein kinases and sensitive to the activation of metabotropic glutamate receptors.

Iron entry in neurons and astrocytes: a link with synaptic activity.

Iron plays a fundamental role in the development of the central nervous system (CNS) as well as in several neuronal functions including synaptic plasticity. Accordingly, neuronal iron supply is tightly controlled: it depends not only on transferrin-bound iron but also on non-transferrin-bound iron (NTBI), which represents a relevant quote of the iron physiologically present in the cerebrospinal fluid (CSF). Different calcium permeable channels as well as the divalent metal transporter 1 (DMT1) have been proposed to sustain NTBI entry in neurons and astrocytes even though it remains an open issue.

Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia.

Background: Ceruloplasmin is a ferroxidase expressed in the central nervous system both as soluble form in the cerebrospinal fluid (CSF) and as membrane-bound GPI-anchored isoform on astrocytes, where it plays a role in iron homeostasis and antioxidant defense. It has been proposed that ceruloplasmin is also able to activate microglial cells with ensuing nitric oxide (NO) production, thereby contributing to neuroinflammatory conditions. In light of the possible role of ceruloplasmin in neurodegenerative diseases, we were prompted to investigate how this protein could contribute to microglial activation in either its native form, as well as in its oxidized form, recently found generated in the CSF of patients with Parkinson's and Alzheimer's diseases.

Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis.

Calcitonin Gene-Related Peptide (CGRP) inhibits microglia inflammatory activation in vitro. We here analyzed the involvement of CGRP and Receptor Component Protein (RCP) in experimental autoimmune encephalomyelitis (EAE). Alpha-CGRP deficiency increased EAE scores which followed the scale alpha-CGRP null>heterozygote>wild type.

Metallothioneins as dynamic markers for brain disease in lysosomal disorders.

Objective: To facilitate development of novel disease-modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD.

Methods: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls.

Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation.

Background: Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as "activation", is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels.

Iron uptake in quiescent and inflammation-activated astrocytes: a potentially neuroprotective control of iron burden.

Astrocytes play a crucial role in proper iron handling within the central nervous system. This competence can be fundamental, particularly during neuroinflammation, and neurodegenerative processes, where an increase in iron content can favor oxidative stress, thereby worsening disease progression. Under these pathological conditions, astrocytes undergo a process of activation that confers them either a beneficial or a detrimental role on neuronal survival.

Expression of divalent metal transporter 1 in primary hippocampal neurons: reconsidering its role in non-transferrin-bound iron influx.

The divalent metal transporter 1 (DMT1) is the best characterized Fe²⁺ transporter involved in cellular iron uptake in mammals. Four possible isoforms have been identified as a result of alternative promoter (DMT1-1A and DMT1-1B) and alternative splicing involving the C-terminus and producing transcripts with or without an iron responsive element [DMT1-IRE⁺ and DMT1-IRE⁻, respectively]. Despite the general importance of DMT1 in controlling iron homeostasis, the distribution and the role of the transporter in the CNS is still controversial.

Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin.

Calcitonin gene related peptide (CGRP) and adrenomedullin are potent biologically active peptides that have been proposed to play an important role in vascular and inflammatory diseases. Their function in the central nervous system is still unclear since they have been proposed as either pro-inflammatory or neuroprotective factors. We investigated the effects of the two peptides on astrocytes and microglia, cells of the central nervous system that exert a strong modulatory activity in the neuroinflammatory processes.

Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity.

The characterization of iron handling in neurons is still lacking, with contradictory and incomplete results. In particular, the relevance of non-transferrin-bound iron (NTBI), under physiologic conditions, during aging and in neurodegenerative disorders, is undetermined. This study investigates the mechanisms underlying NTBI entry into primary hippocampal neurons and evaluates the consequence of iron elevation on neuronal viability.

β-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression.

BACE1 and BACE2 are two closely related membrane-bound aspartic proteases. BACE1 is widely recognized as the neuronal β-secretase that cleaves the amyloid-β precursor protein, thus allowing the production of amyloid-β, i.e.

Calcitonin gene-related peptide (CGRP) stimulates purkinje cell dendrite growth in culture.

Previous reports described the transient expression during development of Calcitonin Gene-Related Peptide (CGRP) in rodent cerebellar climbing fibers and CGRP receptor in astrocytes. Here, mixed cerebellar cultures were used to analyze the effects of CGRP on Purkinje cells growth. Our results show that CGRP stimulated Purkinje cell dendrite growth under cell culture conditions mimicking Purkinje cell development in vivo.

Iron and calcium in the central nervous system: a close relationship in health and sickness.

Iron and calcium are required for general cellular functions, as well as for specific neuronal-related activities. However, a pathological increase in their levels favours oxidative stress and mitochondrial damage, leading to neuronal death. Neurodegeneration can thus be determined by alterations in ionic homoeostasis and/or pro-oxidative-antioxidative equilibrium, two conditions that vary significantly in different kinds of brain cell and also with aging.

Sphingosylphosphocholine effects on cultured astrocytes reveal mechanisms potentially involved in neurotoxicity in Niemann-Pick type A disease.

Niemann-Pick type A is a disease characterized by the absence of a functional SMPD1 (acidic sphingomyelinase) gene and the abnormal accumulation of sphingomyelin. Under these conditions, also sphingosylphosphocholine (SPC, a sphingomyelin metabolite) accumulates in various tissues, including the brain, where it might act as a toxic stimulus, contributing to the appearance of the neurological symptoms. We studied the effects of SPC on astrocytic and neuronal cultures from rat.

BACE1 expression and activity: relevance in Alzheimer's disease.

A turning point of research in Alzheimer's disease was undoubtedly the discovery of BACE1, the amyloid-beta precursor protein-cleaving enzyme that initiates the generation of amyloid-beta, the peptide strongly suspected to be responsible for neuronal malfunction and death. Several research groups started a race to identify the best inhibitor of BACE1 activity. On the other hand, basic researchers are evaluating the changes in BACE1 expression and activity with the aim to better understand the pathogenetic process of the disease.

Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region.

BACE1 is the protease responsible for the production of amyloid-beta peptides that accumulate in the brain of Alzheimer's disease (AD) patients. BACE1 expression is regulated at the transcriptional, as well as post-transcriptional level. Very high BACE1 mRNA levels have been observed in pancreas, but the protein and activity were found mainly in brain.

EP2 receptor stimulation promotes calcium responses in astrocytes via activation of the adenylyl cyclase pathway.

Astrocytes are a heterogeneous population of cells that are endowed with a great variety of receptors for neurotransmitters and neuromodulators. Recently prostaglandin E2 has attracted great interest since it is not only released by astrocytes but also activates receptors coupled to either phospholipase C or adenylyl cyclase. We report that EP2 receptor stimulation triggers cAMP production but also causes release of Ca2+ from intracellular stores.