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.

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.

Positive Touch Deprivation during the COVID-19 Pandemic: Effects on Anxiety, Stress, and Depression among Italian General Population.

Physical distancing due to the COVID-19 Pandemic has limited the opportunities for family members, friends, and significant others to show physical affection (i.e., hugs, kisses, caresses, holding hands) during social interactions.

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 Antifungal Antibiotic Filipin as a Diagnostic Tool of Cholesterol Alterations in Lysosomal Storage Diseases and Neurodegenerative Disorders.

Cholesterol is the most considerable member of a family of polycyclic compounds understood as sterols, and represents an amphipathic molecule, such as phospholipids, with the polar hydroxyl group located in position 3 and the rest of the molecule is completely hydrophobic. In cells, it is usually present as free, unesterified cholesterol, or as esterified cholesterol, in which the hydroxyl group binds to a carboxylic acid and thus generates an apolar molecule. Filipin is a naturally fluorescent antibiotic that exerts a primary antifungal effect with low antibacterial activity, interfering with the sterol stabilization of the phospholipid layers and favoring membrane leakage.

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer's Disease: Implications for Diagnosis and Treatment.

Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)-whose causes are not completely understood-and familial (FAD)-with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau).

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.

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.

Stress-Induced Reduction of Dorsal Striatal D2 Dopamine Receptors Prevents Retention of a Newly Acquired Adaptive Coping Strategy.

The inability to learn an adaptive coping strategy in a novel stressful condition leads to dysfunctional stress coping, a marker of mental disturbances. This study tested the involvement of dorsal striatal dopamine receptors in the dysfunctional coping with the Forced Swim test fostered by a previous experience of reduced food availability. Adult male mice were submitted to a temporary (12 days) reduction of food availability [food-restricted (FR)] or continuously free-fed (FF).

Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease.

The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to the Sonic hedgehog (Shh) receptor, Patched, and involved in intracellular trafficking of cholesterol. We have recently found that the proliferation of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression. This finding prompted us to analyze the formation of the primary cilium, a non-motile organelle that is specialized for Shh signal transduction and responsible, when defective, for several human genetic disorders.

Sexually Dimorphic Expression of Reelin in the Brain of a Mouse Model of Alzheimer Disease.

Recent evidence highlights the protective role of reelin against amyloid β (Aβ)-induced synaptic dysfunction and cognitive impairment in Alzheimer disease (AD). In this study, exploiting TgCRND8 mice that overexpress a mutant form of amyloid β precursor protein (AβPP) and display an early onset of AD neuropathological signs, we addressed the question whether changes of reelin expression eventually precede the appearance of Aβ-plaques in a sex-dependent manner. We show that sex-associated and brain region-specific differences in reelin expression appear long before Aβ-plaque formation.

Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.

Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice.

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin.

Background: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected.

Both the COMT Val158Met single-nucleotide polymorphism and sex-dependent differences influence response inhibition.

Reactive and proactive controls of actions are cognitive abilities that allow one to deal with a continuously changing environment by adjusting already programmed actions. They also set forthcoming actions by evaluating the outcome of the previous ones. Earlier studies highlighted sex-related differences in the strategies and in the pattern of brain activation during cognitive tasks involving reactive and proactive control.

Multiple TSC22D4 iso-/phospho-glycoforms display idiosyncratic subcellular localizations and interacting protein partners.

Proteins of the TSC22 domain (TSC22D) family, including TSC22D1 and TSC22D4, play pivotal roles in cell proliferation, differentiation and apoptosis, interacting with other factors in a still largely unknown manner. This study explores this issue by biochemically characterizing various TSC22D4 forms (both iso- and glyco-phospho-, namely the splice variants 42 and 55 kDa and the post-translationally modified 67 and 72 kDa forms) and their subcellular localization and protein partners during cerebellar granule neuron (CGN) differentiation. The TSC22D4-42 form is mostly cytosolic, and is the only TSC22D4 form that associates with TSC22D1.