Human Neurological Disorders Research Articles

PigSNIPE: Scalable Neuroimaging Processing Engine for Minipig MRI

Translation of basic animal research to find effective methods of diagnosing and treating human neurological disorders requires parallel analysis infrastructures. Small animals such as mice provide exploratory animal disease models. However, many interventions developed using small animal models fail to translate to human use due to physical or biological differences. Recently, large-animal minipigs have emerged in neuroscience due to both their brain similarity and economic advantages. Medical image processing is a crucial part of research, as it allows researchers to monitor their experiments and understand disease development. By pairing four reinforcement learning models and five deep learning UNet segmentation models with existing algorithms, we developed PigSNIPE, a pipeline for the automated handling, processing, and analyzing of large-scale data sets of minipig MR images. PigSNIPE allows for image registration, AC-PC alignment, detection of 19 anatomical landmarks, skull stripping, brainmask and intracranial volume segmentation (DICE 0.98), tissue segmentation (DICE 0.82), and caudate-putamen brain segmentation (DICE 0.8) in under two minutes. To the best of our knowledge, this is the first automated pipeline tool aimed at large animal images, which can significantly reduce the time and resources needed for analyzing minipig neuroimages.

The heat shock protein DNAJB2 as a novel biomarker for essential thrombocythemia diagnosis associated with immune infiltration

Background and objectiveEssential thrombocythemia (ET) is a rare myeloproliferative malignancy which may lead to severe thrombohemorrhagic complications. The diagnosis of ET is primarily based on bone marrow morphology and exclusion of other possibilities of myeloproliferative neoplastic diseases; the lack of gene biomarkers fails to provide a prompt diagnosis of ET. Therefore, this study was designed to identify biomarkers for early ET diagnosis, especially that associated with immune cell infiltration, by using the Gene Expression Omnibus (GEO) database and machine-learning algorithms. MethodsTwo publicly available gene expression profiles (GSE9827 and GSE123732) from the GEO database were used to identify the differentially expressed genes (DEGs) between bone marrow samples of ET patients and healthy individuals, and functional enrichment analyses were conducted. The least absolute shrinkage and selection operator (LASSO) regression model and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) machine-learning algorithm were performed to select the candidate gene biomarker. The expression level and diagnostic effectiveness of the identified gene biomarker were further validated using GSE567 and GSE2006 datasets. The involvement of infiltrating immune cells and their correlations with the gene biomarker were examined using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. ResultsThere were 105 DEGs identified between ET and healthy control samples. Disease Ontology (DO) analysis showed that the diseases enriched by those DEGs were mainly human cancers, neurological diseases and inflammation while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that pathways related to immune responses were primarily involved. The heat shock protein, DNAJB2, was identified as the potential biomarker for ET diagnosis with high effectiveness, with the area under the receiver operating characteristic (ROC) curve (AUC) equals to 0.905 in the validation cohort. The expression level of DNAJB2 in ET samples was indeed significantly higher than that in healthy control ones. The immune cell infiltration analysis showed that DNAJB2 was positively correlated with CD8+ T cells in ET with the proportion significantly higher than that in normal controls. ConclusionThe present study identified DNAJB2 as a novel diagnostic biomarker for ET with high effectiveness based on ET and normal samples from the GEO database, which provides new insights into predicting ET with accuracy and promptness in clinical practice.

NOVA1 acts on Impact to regulate hypothalamic function and translation in inhibitory neurons.

We describe a patient haploinsufficient for the neuronal RNA binding protein NOVA1 who developed a behavioral motor hyperactivity disorder, suggesting a role of NOVA1 in postnatal motor inhibition. To investigate Nova1's action in adult Gad2+ inhibitory neurons, we generated a conditional Nova1-null mouse (Nova1-cKOGad2-cre). Strikingly, the phenotypes of these mice show many similarities to the NOVA1 haploinsufficient patient and identify a function of Nova1 in the hypothalamus. Molecularly, Nova1 loss in Gad2-positive neurons alters downstream expression of Impact mRNA, along with a subset of RNAs encoding electron transport chain-related factors and ribosomal proteins. NOVA1 stabilizes Impact mRNA by binding its 3' UTR, antagonizing the actions of miR-138 and miR-124. Together, these studies demonstrate actions of NOVA1 in adult hypothalamic neurons, mechanisms by which it functions in translation and metabolism, including through direct binding to Impact mRNA, and illuminate its role in human neurologic disease.

Structure of the shaker Kv channel in low K and mechanism of slow C-type inactivation.

Voltage-activated potassium (Kv) channels open upon membrane depolarization and proceed to spontaneously inactivate. Inactivation controls neuronal firing and serves as a form of short-term memory and is implicated in various human neurological disorders. Inactivation can proceed through two distinct mechanisms: a fast ball-and-chain mechanism that blocks the inner pore, and a slower C-type mechanism that disables the ion selectivity filter. In our previous study, we determined the structures of the Shaker Kv channel and the C-type inactivated W434F mutant in 150 mM KCl condition. The Shaker Kv channel exhibits an open internal pore and the selectivity filter within the external pore in a conducting state. By contrast, the W434F mutant exhibits a 4 Å dilation of the external half of the ion selectivity filter and the repositioning of neighboring residues known to be critical for C-type inactivation. To further confirm whether the conformational change in W434F mutant is representative of C-type inactivation in the wild-type Shaker Kv channel, we solved the structure of Shaker in 4 mM KCl, a condition known to favor inactivation. The structure of Shaker in low KCl is higher resolution than structures solved in high KCl, yet otherwise is remarkably similar to the structure of the W434F. We conclude that slow C-type inactivation in the Shaker Kv channels results in localized conformational change that disrupts potassium ion binding sites by dilating the external end of the filter.

Melatonin Can Modulate Neurodegenerative Diseases by Regulating Endoplasmic Reticulum Stress.

As people age, their risks of developing degenerative diseases such as cancer, diabetes, Parkinson's Disease (PD), Alzheimer's Disease (AD), rheumatoid arthritis, and osteoporosis are generally increasing. Millions of people worldwide suffer from these diseases as they age. In most countries, neurodegenerative diseases are generally recognized as the number one cause afflicting the elderly. Endoplasmic reticulum (ER) stress has been suggested to be associated with some human neurological diseases, such as PD and AD. Melatonin, a neuroendocrine hormone mainly synthesized in the pineal gland, is involved in pleiotropically biological functions, including the control of the circadian rhythm, immune enhancement, and antioxidant, anti-aging, and anti-tumor effects. Although there are many papers on the prevention or suppression of diseases by melatonin, there are very few papers about the effects of melatonin on ER stress in neurons and neurodegenerative diseases. This paper aims to summarize and present the effects of melatonin reported so far, focusing on its effects on neurons and neurodegenerative diseases related to ER stress. Studies have shown that the primary target molecule of ER stress for melatonin is CHOP, and PERK and GRP78/BiP are the secondary target molecules. Therefore, melatonin is crucial in protecting neurons and treating neurodegeneration against ER stress.

Programmable macromolecule-based RNA-targeting therapies to treat human neurological disorders.

Disruptions in RNA processing play critical roles in the pathogenesis of neurological diseases. In this Perspective, we discuss recent progress in the development of RNA-targeting therapeutic modalities. We focus on progress, limitations, and opportunities in a new generation of therapies engineered from RNA binding proteins and other endogenous RNA regulatory macromolecules to treat human neurological disorders.

Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition

RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. However, the mechanism for aggregation—including how aggregation properties change with sequence and environmental conditions—remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington’s disease, and enabling the rational design of programmable RNA condensates.

Altered gut microbiota in individuals with episodic and chronic migraine

Emerging evidence reveals a close association between gut microbiota and human neurological disorders. The present study aimed to assess whether the composition of gut microbiota in participants with episodic migraine (EM) and chronic migraine (CM) was altered in comparison to that of the controls. This study was a cross-sectional, case–control study. The gut microbiota were evaluated by the partial, targeted sequencing of the 16S rRNA V3–V4 region. This study enrolled 42 and 45 participants with EM and CM, respectively, and 43 controls. Alpha and beta diversities revealed no significant difference among the three groups; however, the microbiota composition at the class, order, family, and genus levels differed significantly between EM and the control, CM and the control, and the EM and CM groups. Moreover, higher composition of PAC000195_g was significantly associated with a lower headache frequency among the five genera that exhibited significantly different microbiota composition in EM and CM. Agathobacter revealed a significant negative association with severe headache intensity. The findings of the present study provide evidence of altered gut microbiota in EM and CM. These findings will help in understanding the course and treatment of migraine.

Ferret Models for Henipavirus Infection.

Henipaviruses are emerging zoonotic viruses that can cause outbreaks of severe respiratory and neurological disease in humans and animals such as horses. The mechanism by which these viruses can cause disease remain largely unknown and to date there are no therapeutics or vaccines approved for use in humans. Nipah virus is listed on the World Health Organization R & D Blueprint list of epidemic threats. In order to advance the availability of effective therapeutics and vaccines and medicines that can be used to save lives and avert large scale crises, animal models are required which recapitulate the disease progression in humans. Ferrets are highly susceptible to infection with henipaviruses and develop both severe respiratory and neurological disease. Therefore, the ferret model is highly suitable for studies into both the pathogenesis of henipaviruses, as well as pre-clinical evaluation of intervention strategies.

The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile.

Circular RNAs (circRNAs) are a class of non-coding RNAs increasingly emerging as crucial actors in the pathogenesis of human diseases, including autoimmune and neurological disorders as multiple sclerosis (MS). Despite several efforts, the mechanisms regulating circRNAs expression are still largely unknown and the circRNA profile and regulation in MS-relevant cell models has not been completely investigated. In this work, we aimed at exploring the global landscape of circRNA expression in MS patients, also evaluating a possible correlation with their genetic and epigenetic background. We performed RNA-seq experiments on circRNA-enriched samples, derived from peripheral blood mononuclear cells (PBMCs) of 10 MS patients and 10 matched controls and performed differential circRNA expression. The genetic background was evaluated using array genotyping, and an expression quantitative trait loci (eQTL) analysis was carried out. Expression analysis revealed 166 differentially expressed circRNAs in MS patients, 125 of which are downregulated. One of the top dysregulated circRNAs, hsa_circ_0007990, derives from the PGAP3 gene, encoding a protein relevant for the control of autoimmune responses. The downregulation of this circRNA was confirmed in two independent replication cohorts, suggesting its implementation as a possible RNA-based biomarker. The eQTL analysis evidenced a significant association between 89 MS-associated loci and the expression of at least one circRNA, suggesting that MS-associated variants could impact on disease pathogenesis by altering circRNA profiles. Finally, we found a significant correlation between exon methylation and circRNA expression levels, supporting the hypothesis that epigenetic features may play an important role in the definition of the cell circRNA pool. We described the circRNA expression profile of PBMCs in MS patients, suggesting that MS-associated variants may tune the expression levels of circRNAs acting as "circ-QTLs", and proposing a role for exon-based DNA methylation in regulating circRNA expression.

Characterizing the Neuron-Glial Interactions by the Co-cultures of Human iPSC-Derived Oligodendroglia and Neurons.

Induced pluripotent stem cell (iPSC) techniques have had considerable breakthroughs in modeling human neurological diseases. Multiple protocols inducing neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells have been well-established thus far. However, these protocols have limitations, including the long time period to get cells of interest or the challenge of culturing more than one cell type simultaneously. Protocols for handling multiple cell types within a shorter time period are still being established. Here we describe a simple and reliable co-culture system to study interactions between neurons and oligodendrocyte precursor cells (OPC) in health and in disease.

Therapeutic Potential of Active Components from Acorus gramineus and Acorus tatarinowii in Neurological Disorders and Their Application in Korean Medicine.

Neurological disorders represent a substantial healthcare burden worldwide due to population aging. Acorus gramineus Solander (AG) and Acorus tatarinowii Schott (AT), whose major component is asarone, have been shown to be effective in neurological disorders. This review summarized current information from preclinical and clinical studies regarding the effects of extracts and active components of AG and AT (e.g., α-asarone and β-asarone) on neurological disorders and biomedical targets, as well as the mechanisms involved. Databases, including PubMed, Embase, and RISS, were searched using the following keywords: asarone, AG, AT, and neurological disorders, including Alzheimer's disease, Parkinson's disease, depression and anxiety, epilepsy, and stroke. Meta-analyses and reviews were excluded. A total of 873 studies were collected. A total of 89 studies were selected after eliminating studies that did not meet the inclusion criteria. Research on neurological disorders widely reported that extracts or active components of AG and AT showed therapeutic efficacy in treating neurological disorders. These components also possessed a wide array of neuroprotective effects, including reduction of pathogenic protein aggregates, antiapoptotic activity, modulation of autophagy, anti-inflammatory and antioxidant activities, regulation of neurotransmitters, activation of neurogenesis, and stimulation of neurotrophic factors. Most of the included studies were preclinical studies that used in vitro and in vivo models, and only a few clinical studies have been performed. Therefore, this review summarizes the current knowledge on AG and AT therapeutic effects as a basis for further clinical studies, and clinical trials are required before these findings can be applied to human neurological disorders.

The Effect of Intraperitoneal Administration of Oleuropein on Pentylenetetrazole Induced Epilepsy in Mail Rat

Background & Objective: Epilepsy is one of the most common neurological disorders in humans, which appears as sudden, episodic, repetitive, and unpredictable seizures, and these patients suffer from memory impairment. Medicinal herbs have long been used to treat epilepsy. In this study, the impact of effective oleuropein on the time of arising of attacks and the rate of attack’s incidence of tonic, clonic, tonic-clonic, and total seizure longevity in male rats was investigated.
 Materials & Methods: Forty rats were randomly divided into four groups of 10. The negative control group (the recipient of normal saline), the positive control group (the recipient of diazepam 1 mg/kg), and the two treatment groups (the recipient of doses of 10 and 20 mg/kg of oleuropein). After 30 min of oleuropein administration, saline, or diazepam, pentylenetetrazole was injected intraperitoneally into rats’ bodies at a dose of 85 mg/kg, and 30 min after injection, seizure parameters were evaluated. Data were analyzed by one-way ANOVA and Tukey’s statistical tests.
 Results: Injection of the oleuropein significantly increased the threshold of seizures in the form of initial delay at the arising of seizure in the positive control group and treatment groups (P< 0.001). Furthermore, it reduces the time of seizures in different phases (P< 0.001). In addition, a dose of 10 mg/kg oleuropein has the highest effect on total seizure longevity.
 Conclusion: This study showed that oleuropein has an appropriate anti-seizure effect and future studies appear to be necessary for further understanding of the mechanism.

The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation.

Many human cardiovascular and neurological disorders (such as ischemia, epileptic seizures, traumatic brain injury, neuropathic pain, etc.) are associated with the abnormal functional activity of voltage-gated sodium channels (VGSCs/NaVs). Many natural toxins, including the sea anemone toxins (called neurotoxins), are an indispensable and promising tool in pharmacological researches. They have widely been carried out over the past three decades, in particular, in establishing different NaV subtypes functional properties and a specific role in various pathologies. Therefore, a large number of publications are currently dedicated to the search and study of the structure-functional relationships of new sea anemone natural neurotoxins-potential pharmacologically active compounds that specifically interact with various subtypes of voltage gated sodium channels as drug discovery targets. This review presents and summarizes some updated data on the structure-functional relationships of known sea anemone neurotoxins belonging to four structural types. The review also emphasizes the study of type 2 neurotoxins, produced by the tropical sea anemone Heteractis crispa, five structurally homologous and one unique double-stranded peptide that, due to the absence of a functionally significant Arg14 residue, loses toxicity but retains the ability to modulate several VGSCs subtypes.

Recent Development of Brain Organoids for Biomedical Application.

Over the years, scientists have studied the behavior and anatomy of many animals to understand the own species. However, despite the continuous efforts, it is often difficult to know for certain how the brain works due to the differences between the brains of animals and the human brain. While the use of animal models for research continues, the origin of human cognition and neurological disorders needs further elucidation. To that end, in vitro organoids that exhibit in vivo characteristics of the human brain have been recently developed. These brain-like organoids enable researchers to dive deeper into understanding the human brain, its neurological structures, and the causes of neurological pathologies. This paper reviews the recent developments in the regeneration of brain-like organoids using Matrigel and other alternatives. Further, gel-free methods that may enhance the regeneration process of organoids are discussed. Finally, the vascularized brain organoid growth and development in both in vitro and in vivo conditions are detailed.

Saffron against Neuro-Cognitive Disorders: An Overview of Its Main Bioactive Compounds, Their Metabolic Fate and Potential Mechanisms of Neurological Protection.

Saffron (Crocus sativus L.) is a spice used worldwide as a colouring and flavouring agent. Saffron is also a source of multiple bioactive constituents with potential health benefits. Notably, saffron displays consistent beneficial effects against a range of human neurological disorders (depression, anxiety, sleeping alterations). However, the specific compounds and biological mechanisms by which this protection may be achieved have not yet been elucidated. In this review, we have gathered the most updated evidence of the neurological benefits of saffron, as well as the current knowledge on the main saffron constituents, their bioavailability and the potential biological routes and postulated mechanisms by which the beneficial protective effect may occur. Our aim was to provide an overview of the neuroprotective effects attributed to this product and its main bioactive compounds and to highlight the main research gaps that need to be further pursued to achieve full evidence and understanding of the benefits of saffron. Overall, improved clinical trials and adequately designed pre-clinical studies are needed to support the evidence of saffron and of its main bioactive components (e.g., crocin, crocetin) as a therapeutic product to combat neurological disorders.

What connects splicing of transfer RNA precursor molecules with pontocerebellar hypoplasia?

Transfer RNAs (tRNAs) represent the most abundant class of RNA molecules in the cell and are key players during protein synthesis and cellular homeostasis. Aberrations in the extensive tRNA biogenesis pathways lead to severe neurological disorders in humans. Mutations in the tRNA splicing endonuclease (TSEN) and its associated RNA kinase cleavage factor polyribonucleotide kinase subunit 1 (CLP1) cause pontocerebellar hypoplasia (PCH), a heterogeneous group of neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by microcephaly, profound motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature tRNA ratios in patient-derived cells. However, how tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis.

Phosphatidylinositol (3,5)-bisphosphate machinery regulates neurite thickness through neuron-specific endosomal protein NSG1/NEEP21

Phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] is a critical signaling phospholipid involved in endolysosome homeostasis. It is synthesized by a protein complex composed of PIKfyve, Vac14, and Fig4. Defects in PtdIns(3,5)P2 synthesis underlie a number of human neurological disorders, including Charcot-Marie-Tooth disease, child onset progressive dystonia, and others. However, neuron-specific functions of PtdIns(3,5)P2 remain less understood. Here, we show that PtdIns(3,5)P2 pathway is required to maintain neurite thickness. Suppression of PIKfyve activities using either pharmacological inhibitors or RNA silencing resulted in decreased neurite thickness. We further find that the regulation of neurite thickness by PtdIns(3,5)P2 is mediated by NSG1/NEEP21, a neuron-specific endosomal protein. Knockdown of NSG1 expression also led to thinner neurites. mCherry-tagged NSG1 colocalized and interacted with proteins in the PtdIns(3,5)P2 machinery. Perturbation of PtdIns(3,5)P2 dynamics by overexpressing Fig4 or a PtdIns(3,5)P2-binding domain resulted in mislocalization of NSG1 to nonendosomal locations, and suppressing PtdIns(3,5)P2 synthesis resulted in an accumulation of NSG1 in EEA1-positive early endosomes. Importantly, overexpression of NSG1 rescued neurite thinning in PtdIns(3,5)P2-deficient CAD neurons and primary cortical neurons. Our study uncovered the role of PtdIns(3,5)P2 in the morphogenesis of neurons, which revealed a novel aspect of the pathogenesis of PtdIns(3,5)P2-related neuropathies. We also identified NSG1 as an important downstream protein of PtdIns(3,5)P2, which may provide a novel therapeutic target in neurological diseases.

Recent Advances in Brain Organoid Technology for Human Brain Research.

Brain organoids are self-assembled three-dimensional aggregates with brain-like cell types and structures and have emerged as new model systems that can be used to investigate human neurodevelopment and neurological disorders. However, brain organoids are not as mature and functional as real human brains due to limitations of the culture system with insufficient developmental patterning signals and a lack of components that are important for brain development and function, such as the non-neural population and vasculature. In addition, establishing the desired brain-like environment and monitoring the complex neural networks and physiological functions of the brain organoids remain challenging. The current protocols to generate brain organoids also have problems with heterogeneity and batch variation due to spontaneous self-organization of brain organoids into complex architectures of the brain. To address these limitations of current brain organoid technologies, various engineering platforms, such as extracellular matrices, fluidic devices, three-dimensional bioprinting, bioreactors, polymeric scaffolds, microelectrodes, and biochemical sensors, have been employed to improve neuronal development and maturation, reduce structural heterogeneity, and facilitate functional analysis and monitoring. In this review, we provide an overview of the latest engineering techniques that overcome these limitations in the production and application of brain organoids.

Impact of Environmental Pollutants on Alzheimer’s Disease: A Review

Environmental pollution is one of the major concerns as it affects public health and is responsible for various neurological disorders too. Neurological disorders are governed by many different factors - they can be genetic, based on lifestyle, or environmental. In many recent studies, it has been observed that exposure to many environmental pollutants increases the risk of Alzheimer’s disease (AD). Pollutants like PM 10, PM2.5, and some other ultrafine nanoparticles, lipophilic vaporized toxicant (acrolein) can easily reach the brain by crossing the blood-brain barrier after it they can activate the innate immune responses inside the target site like neurons, astrocytes, and microglia by this way they can be neurotoxic. Human epidemiological evidence proves that there is a correlation between environmental pollutants and neurological disorders like dysfunction of mitochondrial, oxidative stress, disruption in the myelin sheath, the blood-brain barrier anatomy alterations, and endoplasmic reticulum stress which direct towards cognitive impairment with lower quality of lifestyle. The review article aims to culminate the correlation between the environmental factors and Alzheimer’s disease, The different sources of pollution and their effect on various stages of human life, developmental neurotoxicity, and neurological disorders also have been discussed.