The inactivation of the Niemann Pick C1 cholesterol transporter restricts SARS-CoV-2 entry into host cells by decreasing ACE2 abundance at the plasma membrane.

Background: The Niemann Pick C1 (NPC1) protein is an intracellular cholesterol transporter located in the late endosome/lysosome (LE/Ly) that is involved in the mobilization of endocytosed cholesterol. Loss-of-function mutations in the NPC1 gene lead to the accumulation of cholesterol and sphingolipids in LE/Ly, resulting in severe fatal NPC1 disease. Cellular alterations associated with NPC1 inactivation affect both the integrity of lipid rafts and the endocytic pathway.

Genotype-dependent functional role of the anterior and posterior paraventricular thalamus in pavlovian conditioned approach.

Rationale: The specific location of deviations from normative models of brain function varies considerably across individuals with the same diagnoses. However, as pathological processes are distributed across interconnected systems, this heterogeneity of individual brain deviations may also reveal similarities and differences between disorders. The paraventricular nucleus of the thalamus (PVT) is a potential switcher to various behavioral responses where functionally distinct cell types exist across its antero-posterior axis.

Cognitive Empathy and the Dark Triad: A Literature Review.

This literature review aims to analyze studies published by researchers on the topic of the relationship between the psychological constructs of the Dark Triad and Cognitive Empathy. This study hypothesizes how having good cognitive empathic skills could benefit people who demonstrate Dark Triad traits, as this could facilitate the implementation of manipulative strategies. Through the process of identifying studies via databases and registers, 23 studies were included in this literature review, and the results and theories brought forward by the researchers find more agreement regarding the individual components of the Dark Triad than the whole construct: narcissism seems to have, for the most part, relatively small and typical positive correlations (more than 50% of correlations), Machiavellianism has relatively small and typical negative relationships (about 80% of correlations), and psychopathy has relatively large negative relationships (about 90% of correlations).

Endocannabinoid signaling in adult hippocampal neurogenesis: A mechanistic and integrated perspective.

Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain throughout life. Within this neurogenic region, the fate and behavior of neural stem cells (NSCs) and their progeny result from a complex balance and integration of a variety of cell-autonomous and cell-to-cell-interaction signals and underlying pathways. Among these structurally and functionally diverse signals, there are endocannabinoids (eCBs), the main brain retrograde messengers.

Reduced Cerebellar BDNF Availability Affects Postnatal Differentiation and Maturation of Granule Cells in a Mouse Model of Cholesterol Dyshomeostasis.

Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder due to mutations in the NPC1 gene resulting in the accumulation of cholesterol within the endosomal/lysosomal compartments. The prominent feature of the disorder is the progressive Purkinje cell degeneration leading to ataxia.In a mouse model of NPC1 disease, we have previously demonstrated that impaired Sonic hedgehog signaling causes defective proliferation of granule cells (GCs) and abnormal cerebellar morphogenesis.

Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials.

Friedreich's ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation.

The Relationship between Orthorexia Nervosa and Obsessive Compulsive Disorder.

Orthorexia nervosa (ON) is characterized by an intense avoidance of foods considered unhealthy, obsession with healthy eating behaviors, and pathological fixation on healthy foods. Although there are still debates in the literature about the psychological factors and symptoms of ON, it should be noted that many of the symptoms share common features with obsessive compulsive disorder (OCD). The aim of the present study was to investigate the relationship between ON and OCD with its subtypes.

Sex differences in antioxidant defence and the regulation of redox homeostasis in physiology and pathology.

Reactive oxygen species (ROS) is a term that defines a group of unstable compounds derived from exogenous sources or endogenous metabolism. Under physiological conditions, low levels of ROS play a key role in the regulation of signal transduction- or transcription-mediated cellular responses. In contrast, excessive and uncontrolled loading of ROS results in a pathological state known as oxidative stress (OS), a leading contributor to aging and a pivotal factor for the onset and progression of many disorders.

The Cerebellum in Niemann-Pick C1 Disease: Mouse Versus Man.

Selective neuronal vulnerability is common to most degenerative disorders, including Niemann-Pick C (NPC), a rare genetic disease with altered intracellular trafficking of cholesterol. Purkinje cell dysfunction and loss are responsible for cerebellar ataxia, which is among the prevailing neurological signs of the NPC disease. In this review, we focus on some questions that are still unresolved.

Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders.

Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the mammalian brain, essential not only to the development of the central nervous system but also to synaptic plasticity. BDNF is present in various brain areas, but highest levels of expression are seen in the cerebellum and hippocampus. After birth, BDNF acts in the cerebellum as a mitogenic and chemotactic factor, stimulating the cerebellar granule cell precursors to proliferate, migrate and maturate, while in the hippocampus BDNF plays a fundamental role in synaptic transmission and plasticity, representing a key regulator for the long-term potentiation, learning and memory.

Sex moderates the association between the COMT Val158Met single-nucleotide polymorphism and disorderliness facet of novelty seeking.

Previous studies have shown inconsistent results regarding the effect of the ValMet polymorphism of the catechol-O-methyltransferase (COMT) gene on personality and cognition. Here, nonclinical Caucasian university students of Italian origin were administered the Temperament and Character Inventory-Revised, Tellegen Absorption Scale, Differential Attentional Processes Inventory, and Waterloo-Stanford Group Scale of Hypnotic Susceptibility. We found that the COMT ValMet polymorphism was significantly associated with the disorderliness facet of novelty seeking (NS4) and that sex was a moderator of this association.

Ferroptosis in Friedreich's Ataxia: A Metal-Induced Neurodegenerative Disease.

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich's Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and antioxidant defenses.

The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia.

Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism.

CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain.

The Presenilin1 () gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-β protein precursor (AβPP), to generate the amyloid-β (Aβ) peptides, involved in Alzheimer's Disease (AD). Other substrates of the γ-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences expression in AD animal models.

Decreased membrane cholesterol in liver mitochondria of the point mutation mouse model of juvenile Niemann-Pick C1, Npc1.

It has long been known that there is decreased mitochondrial function in several tissues of Niemann-Pick C1 model mice and cultured cells. These defects contribute to the accumulation of Reactive Oxygen Species (ROS) and tissue damage. It is also well established that there is increased unesterified cholesterol, stored in late endosomes/lysosomes, in many tissues in mutant humans, mouse models, and mutant cultured cells.

The TCL1 function revisited focusing on metabolic requirements of stemness.

The oncogenic ability of the T-cell leukemia/lymphoma 1 gene, TCL1, has captured the attention in the field of prolymphocytic T-cell and B-cell chronic leukemias for more than two decades. However, the finding that TCL1 is also expressed in totipotent cells of the mouse preimplantation embryos and that it is among the 10 genes, including the transcription factors , and , that are required for maintaining the mitotic self-renewal state of embryonic stem cells, raises a great interest. In this review, we highlight newly acquired evidence pinpointing TCL1 as a crucial regulator of metabolic pathways that dictate somatic cell reprogramming toward pluripotency.

Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos.

Activation of Akt/Protein Kinase B (PKB) by phosphatidylinositol-3-kinase (PI3K) controls several cellular functions largely studied in mammalian cells, including preimplantation embryos. We previously showed that early mouse embryos inherit active Akt from oocytes and that the intracellular localization of this enzyme at the two-cell stage depends on the T-cell leukemia/lymphoma 1 oncogenic protein, Tcl1. We have now investigated whether Akt isoforms, namely Akt1, Akt2 and Akt3, exert a specific role in blastomere proliferation during preimplantation embryo development.

Anomalies in Dopamine Transporter Expression and Primary Cilium Distribution in the Dorsal Striatum of a Mouse Model of Niemann-Pick C1 Disease.

The Niemann-Pick type C1 (NPC1) is a rare genetic disease characterized by the accumulation of endocytosed cholesterol and other lipids in the endosome/lysosome compartments. In the brain, the accumulation/mislocalization of unesterified cholesterol, gangliosides and sphingolipids is responsible for the appearance of neuropathological hallmarks, and progressive neurological decline in patients. The imbalance of unesterified cholesterol and other lipids, including GM2 and GM3 gangliosides, alters a number of signaling mechanisms impacting on the overall homeostasis of neurons.

The interplay between TGF-β-stimulated TSC22 domain family proteins regulates cell-cycle dynamics in medulloblastoma cells.

Proteins belonging to the TGFβ-stimulated clone 22 domain (TSC22D) family display a repertoire of activities, regulating cell proliferation and differentiation. The tumor suppressor activity of the first identified member of the family, TSC22D1 (formerly named TSC-22), has been extensively studied, but afterward a longer isoform encoded by the same gene turned out to play an opposite role. We have previously characterized the role of TSC22D1 and TSC22D4 in cell differentiation using granule neurons (GNs) isolated from the mouse cerebellum.

T Cell Leukemia/Lymphoma 1A is essential for mouse epidermal keratinocytes proliferation promoted by insulin-like growth factor 1.

T Cell Leukemia/Lymphoma 1A is expressed during B-cell differentiation and, when over-expressed, acts as an oncogene in mouse (Tcl1a) and human (TCL1A) B-cell chronic lymphocytic leukemia (B-CLL) and T-cell prolymphocytic leukemia (T-PLL). Furthermore, in the murine system Tcl1a is expressed in the ovary, testis and in pre-implantation embryos, where it plays an important role in blastomere proliferation and in embryonic stem cell (ESC) proliferation and self-renewal. We have also observed that Tcl1-/- adult mice exhibit alopecia and deep ulcerations.

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administration.