GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.

A comprehensive review of peptide toxins vs synthetic modulators of BK channels in Epilepsy

BK channels, or voltage-gated Ca2+ channels, are essential regulators of neuronal excitability and muscular contractions, all of which are abnormal in epilepsy, a chronic neuronal disease. The form, frequency, and transmission of action potentials (APs), as well as neurotransmitter release from presynaptic terminals, are all influenced by BK channels found in the plasma membrane of neurons. Over the last two decades, several naturally occurring BK channel modulators have attracted a lot of attention. The structural and pharmacological properties of BK channel blockers are discussed in this article. The properties of various venom peptide toxins from scorpions and snakes are first identified, with a focus on their distinctive structural motifs, such as their disulfide bond formation pattern, the binding interface between the toxin and the BK channel, and the functional consequences of the toxins' blockage of BK channels. Then, several non-peptide BK channel blockers are discussed, along with their molecular formula and pharmacological impact on BK channels. The precise categorization and explanations of these BK channel blockers are hoped to provide mechanistic insights into BK channel blockade. The structures of peptide toxins and non-peptide compounds may serve as models for the development of new channel blockers, as well as aid in the optimization of lead compounds for use in neurological disorders.

Fatal neuroinvasion of SARS-CoV-2 in K18-hACE2 mice is partially dependent on hACE2 expression

ABSTRACTAnimal models recapitulating the distinctive features of severe COVID-19 are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a lethal model of SARS-CoV-2 infection. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection for up to 14 days post-infection. Despite infection and moderate inflammation in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2. Interestingly, SARS-CoV-2 tropism was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18-hACE2 model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis.SUMMARYCOVID-19 is a respiratory disease caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease, while lung inflammation remains moderate.

More Than Mortar: Glia as Architects of Nervous System Development and Disease

Glial cells are an essential component of the nervous system of vertebrates and invertebrates. In the human brain, glia are as numerous as neurons, yet the importance of glia to nearly every aspect of nervous system development has only been expounded over the last several decades. Glia are now known to regulate neural specification, synaptogenesis, synapse function, and even broad circuit function. Given their ubiquity, it is not surprising that the contribution of glia to neuronal disease pathogenesis is a growing area of research. In this review, we will summarize the accumulated evidence of glial participation in several distinct phases of nervous system development and organization—neural specification, circuit wiring, and circuit function. Finally, we will highlight how these early developmental roles of glia contribute to nervous system dysfunction in neurodevelopmental and neurodegenerative disorders.

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies’ biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies’ consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD’s application on cardiovascular health and on physical performance.

miRNA-Based Rapid Differentiation of Purified Neurons from hPSCs Advancestowards Quick Screening for Neuronal Disease Phenotypes In Vitro

Obtaining differentiated cells with high physiological functions by an efficient, but simple and rapid differentiation method is crucial for modeling neuronal diseases in vitro using human pluripotent stem cells (hPSCs). Currently, methods involving the transient expression of one or a couple of transcription factors have been established as techniques for inducing neuronal differentiation in a rapid, single step. It has also been reported that microRNAs can function as reprogramming effectors for directly reprogramming human dermal fibroblasts to neurons. In this study, we tested the effect of adding neuronal microRNAs, miRNA-9/9*, and miR-124 (miR-9/9*-124), for the neuronal induction method of hPSCs using Tet-On-driven expression of the Neurogenin2 gene (Ngn2), a proneural factor. While it has been established that Ngn2 can facilitate differentiation from pluripotent stem cells into neurons with high purity due to its neurogenic effect, a long or indefinite time is required for neuronal maturation with Ngn2 misexpression alone. With the present method, the cells maintained a high neuronal differentiation rate while exhibiting increased gene expression of neuronal maturation markers, spontaneous calcium oscillation, and high electrical activity with network bursts as assessed by a multipoint electrode system. Moreover, when applying this method to iPSCs from Alzheimer’s disease (AD) patients with presenilin-1 (PS1) or presenilin-2 (PS2) mutations, cellular phenotypes such as increased amount of extracellular secretion of amyloid β42, abnormal oxygen consumption, and increased reactive oxygen species in the cells were observed in a shorter culture period than those previously reported. Therefore, it is strongly anticipated that the induction method combining Ngn2 and miR-9/9*-124 will enable more rapid and simple screening for various types of neuronal disease phenotypes and promote drug discovery.

Research Biomarkers For The Diagnosis Of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neuronal disease that is characterized by the loss of neurons and cognitive impairment. There is no definitive cure and current treatment options are focused more on reducing the damage caused by the disease and providing care for the patients. Early diagnosis of the disease will help in minimizing the damage and give better treatment options. In this review we try to analyze a few important risk factors and identify some biomarkers in blood and cerebrospinal fluid (CSF) which could be used for the diagnosis of AD

Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.

Toward Exosome-Based Neuronal Diagnostic Devices

Targeting exosome for liquid biopsy has gained significant attention for its diagnostic and therapeutic potential. For detecting neuronal disease diagnosis such as Alzheimer’s disease (AD), the main technique for identifying AD still relies on positron-emission tomography (PET) imaging to detect the presence of amyloid-β (Aβ). While the detection of Aβ in cerebrospinal fluid has also been suggested as a marker for AD, the lack of quantitative measurements has compromised existing assays. In cerebrospinal fluid, in addition to Aβ, T-Tau, and P-Tau, alpha-synuclein has been considered a biomarker of neurodegeneration. This review suggests that and explains how the exosome can be used as a neuronal diagnostic component. To this end, we summarize current progress in exosome preparation/isolation and quantification techniques and comment on the outlooks for neuronal exosome-based diagnostic techniques.

Flavonoid-Rich Fraction of Ocimum gratissimum Attenuates Lipopolysaccharide-Induced Sickness Behavior, Inflammatory and Oxidative Stress in Mice

Purpose Ocimum gratissimum L. leaves has been traditionally used for management of febrile illnesses and symptoms typified of sickness behavior. In this work we investigated the modulatory effect of flavonoid-rich fraction of O. gratissimum leaves (EAFOg) on sickness behavior, inflammatory and oxidative stress responses in LPS-challenged mice. Method O. gratissimum leaf was first extracted with n-hexane, chloroform and methanol, and EAFOg was obtained by ethylacetate partitioning of a sequentially resultant methanol extract. The effect of EAFOg (25–100 mg/kg) on acute LPS-induced neurobehavioral impairment in an open field test (OFT) and depressive-like behavior in forced swimming test (FST) was investigated. Serum nitrite and TNF-α, as well as myeloperoxidase (MPO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in liver and brain tissues. Result EAFOg prevented the reduction in locomotor and rearing activity in OFT and the increase in immobility time in FST. The fraction significantly attenuated the elevation of serum TNF- α and nitrite levels. EAFOg reversed LPS-induced increase in MDA, MPO, and nitrite levels and attenuated GSH depletion in liver and brain tissues of mice. Conclusion Flavonoid-rich fraction of O. gratissimum leaf demonstrated significant modulation of LPS-induced sickness behavior, inflammatory and oxidative stress response in mice. This suggests an important therapeutic strategy in slowing down LPS-mediated hepatic and neuronal disease processes.