Genetic causal role of body mass index in multiple neurological diseases.

Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran's Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases.

Non-coding RNAs and neuroinflammation: implications for neurological disorders.

Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

Pathophysiological and therapeutic implications of neuropeptide S system in neurological disorders.

Neuropeptide S (NPS) is a 20 amino acids-containing neuroactive molecule discovered by the reverse pharmacology method. NPS is detected in specific brain regions like the brainstem, amygdala, and hypothalamus, while its receptor (NPSR) is ubiquitously expressed in the central nervous system (CNS). Besides CNS, NPS and NPSR are also expressed in the peripheral nervous system. NPSR is a G-protein coupled receptor that primarily uses Gq and Gs signaling pathways to mediate the actions of NPS. In animal models of Parkinsonism and Alzheimer's disease, NPS exerts neuroprotective effects. NPS suppresses oxidative stress, anxiety, food intake, and pain, and promotes arousal. NPSR facilitates reward, reinforcement, and addiction-related behaviors. Genetic variation and single nucleotide polymorphism in NPSR are associated with depression, schizophrenia, rheumatoid arthritis, and asthma. NPS interacts with several neurotransmitters including glutamate, noradrenaline, serotonin, corticotropin-releasing factor, and gamma-aminobutyric acid. It also modulates the immune system via augmenting pro-inflammatory cytokines and plays an important role in the pathogenesis of rheumatoid arthritis and asthma. In the present review, we discussed the distribution profile of NPS and NPSR, signaling pathways, and their importance in the pathophysiology of various neurological disorders. We have also proposed the areas where further investigations on the NPS system are warranted.

The role of NLRP6 in the development and progression of neurological diseases.

The nervous system possesses the remarkable ability to undergo changes in order to store information; however, it is also susceptible to damage caused by invading pathogens or neurodegenerative processes. As a member of nucleotide-binding oligomerization domain-like receptor (NLR) family, the NLRP6 inflammasome serves as a cytoplasmic innate immune sensor responsible for detecting microbe-associated molecular patterns. Upon activation, NLRP6 can recruit the adapter protein apoptosis-associated speck-like protein (ASC) and the inflammatory factors caspase-1 or caspase-11. Consequently, inflammasomes are formed, facilitating the maturation and secretion of pro-inflammatory cytokines such as inflammatory factors-18 (IL-18) and inflammatory factors-1ß (IL-1ß). Precise regulation of NLRP6 is crucial for maintaining tissue homeostasis, as dysregulated inflammasome activation can contribute to the development of various diseases. Furthermore, NLRP6 may also play a role in the regulation of extraintestinal diseases. In cells of the brain, such as astrocytes and neurons, NLRP6 inflammasome are also present. Here, the assembly and subsequent activation of caspase-1 mediated by NLRP6 contribute to disease progression. This review aims to discuss the structure and function of NLRP6, explain clearly the mechanisms that induce and activate NLRP6, and explore its role within the central and peripheral nervous system.

Bioinformatics and Systems Biology Approaches to Identify the Synergistic Effects of Alcohol Use Disorder on the Progression of Neurological Diseases.

Clinical investigations showed that individuals with Alcohol Use Disorder (AUD) have worse Neurological Disease (ND) development, pointing to possible pathogenic relationships between AUD and NDs. It remains difficult to identify risk factors that are predisposing between AUD and NDs. In order to fix these issues, we created the bioinformatics pipeline and network-based approaches for employing unbiased methods to discover genes abnormally stated in both AUD and NDs and to pinpoint some of the common molecular pathways that might underlie AUD and ND interaction. We found 100 differentially expressed genes (DEGs) in both the AUD and ND patient's tissue samples. The most important Gene Ontology (GO) terms and metabolic pathways, including positive control of cytotoxicity caused by T cells, proinflammatory responses, antigen processing and presentation, and platelet-triggered interactions with vascular and circulating cell pathways were then extracted using the overlapped DEGs. Protein-protein interaction analysis was used to identify hub proteins, including CCL2, IL1B, TH, MYCN, HLA-DRB1, SLC17A7, and HNF4A, in the pathways that have been reported as playing a function in these disorders. We determined several TFs (HNF4A, C4A, HLA-B, SNCA, HLA-DMB, SLC17A7, HLA-DRB1, HLA-C, HLA-A, and HLA-DPB1) and potential miRNAs (hsa-mir-34a-5p, hsa-mir-34c-5p, hsa-mir-449a, hsa-mir-155-5p, and hsa-mir-1-3p) were crucial for regulating the expression of AUD and ND which could serve as prospective targets for treatment. Our methodologies discovered unique putative biomarkers that point to the interaction between AUD and various neurological disorders, as well as pathways that could one day be the focus of therapeutic intervention.

RNA therapeutics for neurological disease.

Neurological disorders are the group of diseases that primarily affect the center nervous system, which could lead to a significant negative impact on the ability of learning new skills, speaking, breathing, walking, judging, making decision, and other essential living skills. In the last decade, neurological disorders have significantly increased their impact to our community and become the one of leading causes of disability and death. The World Health Organization has identified neurological disorders including Alzheimer's disease and other dementia as the health crisis for the modern life. Tremendous ongoing research efforts focus on understanding of disease genetics, molecular mechanisms and developing therapeutic interventions. Because of the urgent need of the effective therapeutics and the recent advances in the toolkits and understanding for developing more drug-like RNA molecules, there is a growing interest for developing RNA therapeutics for neurological disorders. This article will discuss genetics and mechanisms of neurological disorders and how RNA-based molecules have been used to develop therapeutics for this group of diseases, challenges of RNA therapeutics and future perspectives on this rising therapeutic intervention tool.

CRISPR-Based Gene Editing Techniques in Pediatric Neurological Disorders.

The emergence of gene editing technologies offers a unique opportunity to develop mutation-specific treatments for pediatric neurological disorders. Gene editing systems can potentially alter disease trajectory by correcting dysfunctional mutations or therapeutically altering gene expression. Clustered regularly interspaced short palindromic repeats (CRISPR)-based approaches are attractive gene therapy platforms to personalize treatments because of their specificity, ease of design, versatility, and cost. However, many such approaches remain in the early stages of development, with ongoing efforts to optimize editing efficiency, minimize unintended off-target effects, and mitigate pathologic immune responses. Given the rapid evolution of CRISPR-based therapies, it is prudent for the clinically based child neurologist to have a conceptual understanding of what such therapies may entail, including both benefits and risks and how such therapies may be clinically applied. In this review, we describe the fundamentals of CRISPR-based therapies, discuss the opportunities and challenges that have arisen, and highlight preclinical work in several pediatric neurological diseases.

Chromosomal single-strand break repair and neurological disease: Implications on transcription and emerging genomic tools.

Cells are constantly exposed to various sources of DNA damage that pose a threat to their genomic integrity. One of the most common types of DNA breaks are single-strand breaks (SSBs). Mutations in the repair proteins that are important for repairing SSBs have been reported in several neurological disorders. While several tools have been utilised to investigate SSBs in cells, it was only through recent advances in genomics that we are now beginning to understand the architecture of the non-random distribution of SSBs and their impact on key cellular processes such as transcription and epigenetic remodelling. Here, we discuss our current understanding of the genome-wide distribution of SSBs, their link to neurological disorders and summarise recent technologies to investigate SSBs at the genomic level.

Pleiotropic functions of TAO kinases and their dysregulation in neurological disorders.

Thousand and one amino acid kinases (TAOKs) are relatively understudied and functionally pleiotropic protein kinases that have emerged as important regulators of neurodevelopment. Through their conserved amino-terminal catalytic domain, TAOKs mediate phosphorylation at serine/threonine residues in their substrates, but it is their divergent regulatory carboxyl-terminal domains that confer both exquisite functional specification and cellular localization. In this Review, we discuss the physiological roles of TAOKs and the intricate signaling pathways, molecular interactions, and cellular behaviors they modulate-from cell stress responses, division, and motility to tissue homeostasis, immunity, and neurodevelopment. These insights are then integrated into an analysis of the known and potential impacts of disease-associated variants of TAOKs, with a focus on neurodevelopmental disorders, pain and addiction, and neurodegenerative diseases. Translating this foundation into clinical benefits for patients will require greater structural and functional differentiation of the TAOKs afforded by their individually specialized domains.

Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

Assessment of relationships between bullous pemphigoid and neurological diseases: A bidirectional two-sample Mendelian randomization study.

Bullous pemphigoid (BP) is the most prevalent autoimmune vesiculobullous skin illness that tends to affect the elderly. Growing evidence has hinted a correlation between BP and neurological diseases. However, existing observational studies contained inconsistent results, and the causality and direction of their relationship remain poorly understood. To assess the causal relationship between BP and neurological disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and stroke. A bidirectional two-sample Mendelian randomization (MR) adopted independent top genetic variants as instruments from the largest accessible genome-wide association studies (GWASs), with BP (n = 218 348), PD (n = 482 730), AD (n = 63 926), stroke (n = 446 696), and MS (n = 115 803). Inverse variance weighted (IVW), MR-Egger, weighted mode methods, weighted median, and simple mode were performed to explore the causal association. Multiple sensitivity analyses, MR-Pleiotropy Residual Sum and Outlier (PRESSO) was used to evaluate horizontal pleiotropy and remove outliers. With close-to-zero effect estimates, no causal impact of BP on the risk of the four neurological diseases was discovered. However, we found that MS was positively correlated with higher odds of BP (OR = 1.220, 95% CI: 1.058-1.408, p = 0.006), while no causal associations were observed between PD (OR = 0.821, 95% CI: 0.616-1.093, p = 0.176), AD (OR = 1.066, 95% CI: 0.873-1.358, p = 0.603), stroke (OR = 0.911, 95% CI: 0.485-1.713, p = 0.773) and odds of BP. In summary, no causal impact of BP on the risk of PD, AD, MS and stroke was detected in our MR analysis. However, reverse MR analysis identified that only MS was positively correlated with higher odds of BP, but not PD, AD and stroke.

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

An overview of the co-transcription factor NACC1: Beyond its pro-tumor effects.

Nucleus accumbens-associated protein 1 (NACC1) is a member of the broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) protein families, mainly exerting its biological functions as a transcription co-regulator. NACC1 forms homo- or hetero-dimers through the BTB/POZ or BANP, E5R, and NACC1 (BEN) domain with other transcriptional regulators to regulate downstream signals. Recently, the overexpression of NACC1 has been observed in various tumors and is positively associated with tumor progression, high recurrence rate, indicating poor prognosis. NACC1 also regulates biological processes such as embryonic development, stem cell pluripotency, innate immunity, and related diseases. Our review combines recent research to summarize advancements in the structure, biological functions, and relative molecular mechanisms of NACC1. The future development of NACC1 clinical appliances is also discussed.

Causal relationship between coffee intake and neurological diseases: a Mendelian randomization study.

BACKGROUND: Previous observational studies focused on the association of coffee consumption and neurological disease. However, it is not known whether these associations are causal. METHODS: We used Mendelian randomization (MR) study to assess the causal relationship of coffee intake with the risk of neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, and migraine. Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with coffee intake were used as instrumental variable (IV). Genetic instruments were stretched from the MRC-IEU (MRC Integrative Epidemiology Unit) analysis on the UK Biobank. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness. RESULTS: In the MR analysis, 40 SNPs were selected as IV, the F statistics for all SNPs ranged from 16 to 359. In IVW approach, our results provide genetic evidence supporting a potential causal association between coffee intake and a lower risk of migraine (OR = 0.528, 95% CI = 0.342-0.817, P = 0.004) and migraine with aura (OR = 0.374, 95% CI = 0.208-0.672, P = 0.001). However, we found no significant association between coffee intake and other neurological diseases along with their subtypes in this MR study. CONCLUSION: Using genetic data, our MR study found significant evidence supporting a causal association between coffee intake and migraine. This suggests that coffee consumption is likely a trigger or a prevention strategy for migraine.

SCAN: Spatiotemporal Cloud Atlas for Neural cells.

The nervous system is one of the most complicated and enigmatic systems within the animal kingdom. Recently, the emergence and development of spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) technologies have provided an unprecedented ability to systematically decipher the cellular heterogeneity and spatial locations of the nervous system from multiple unbiased aspects. However, efficiently integrating, presenting and analyzing massive multiomic data remains a huge challenge. Here, we manually collected and comprehensively analyzed high-quality scRNA-seq and ST data from the nervous system, covering 10 679 684 cells. In addition, multi-omic datasets from more than 900 species were included for extensive data mining from an evolutionary perspective. Furthermore, over 100 neurological diseases (e.g. Alzheimer's disease, Parkinson's disease, Down syndrome) were systematically analyzed for high-throughput screening of putative biomarkers. Differential expression patterns across developmental time points, cell types and ST spots were discerned and subsequently subjected to extensive interpretation. To provide researchers with efficient data exploration, we created a new database with interactive interfaces and integrated functions called the Spatiotemporal Cloud Atlas for Neural cells (SCAN), freely accessible at http://47.98.139.124:8799 or http://scanatlas.net. SCAN will benefit the neuroscience research community to better exploit the spatiotemporal atlas of the neural system and promote the development of diagnostic strategies for various neurological disorders.

Genetic etiology of progressive pediatric neurological disorders.

BACKGROUND: The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology. METHODS: We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed. RESULTS: We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo. CONCLUSIONS: The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies. IMPACT: Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.

Non-coding RNAs and Aquaporin 4: Their Role in the Pathogenesis of Neurological Disorders.

Neurological disorders are a major group of non-communicable diseases affecting quality of life. Non-Coding RNAs (ncRNAs) have an important role in the etiology of neurological disorders. In studies on the genesis of neurological diseases, aquaporin 4 (AQP4) expression and activity have both been linked to ncRNAs. The upregulation or downregulation of several ncRNAs leads to neurological disorder progression by targeting AQP4. The role of ncRNAs and AQP4 in neurological disorders is discussed in this review.