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Olfactory dysfunction, influenced by factors such as aging and environmental stress, is linked to various neurological disorders. The olfactory bulb's connections to brain areas like the hypothalamus, piriform cortex, entorhinal cortex, and limbic system make olfactory dysfunction a contributor to a range of neuropathological conditions. Recent research has underscored that olfactory deficits are prevalent in individuals with both metabolic syndrome and dementia. These systemic metabolic alterations correlate with olfactory impairments, potentially affecting brain regions associated with the olfactory bulb. In cases of metabolic syndrome, phenomena such as insulin resistance and disrupted glucose metabolism may result in compromised olfactory function, leading to multiple neurological issues. This review synthesizes key findings on the interplay between metabolic-induced olfactory dysfunction and neuropathology. It emphasizes the critical role of olfactory assessment in diagnosing and managing neurological diseases related to metabolic syndrome.
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Síndrome Metabólico , Bulbo Olfatorio , Humanos , Síndrome Metabólico/metabolismo , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/patología , Trastornos del Olfato/metabolismo , Trastornos del Olfato/etiología , Trastornos del Olfato/fisiopatología , Animales , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.
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Biomarcadores , Enfermedades del Sistema Nervioso , Humanos , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/metabolismo , Filamentos Intermedios/metabolismo , AnimalesRESUMEN
Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.
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Encéfalo , Imagen por Resonancia Magnética , Enfermedades del Sistema Nervioso , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Adulto , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/patología , Biopsia , Biopsia Líquida/métodos , Anciano de 80 o más Años , Encefalopatías/patología , Encefalopatías/diagnóstico por imagenRESUMEN
PURPOSE OF REVIEW: The brainstem's complex anatomy and relatively small size means that structural and functional assessment of this structure is done less frequently compared to other brain areas. However, recent years have seen substantial progress in brainstem imaging, enabling more detailed investigations into its structure and function, as well as its role in neuropathology. RECENT FINDINGS: Advancements in ultrahigh field MRI technology have allowed for unprecedented spatial resolution in brainstem imaging, facilitating the new creation of detailed brainstem-specific atlases. Methodological improvements have significantly enhanced the accuracy of physiological (cardiac and respiratory) noise correction within brainstem imaging studies. These technological and methodological advancements have allowed for in-depth analyses of the brainstem's anatomy, including quantitative assessments and examinations of structural connectivity within both gray and white matter. Furthermore, functional studies, including assessments of activation patterns and functional connectivity, have revealed the brainstem's roles in both specialized functions and broader neural integration. Notably, these investigations have identified alterations in brainstem structure and function associated with various neurological disorders. SUMMARY: The aforementioned developments have allowed for a greater appreciation of the importance of the brainstem in the wider context of neuroscience and clinical neurology.
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Tronco Encefálico , Imagen por Resonancia Magnética , Humanos , Tronco Encefálico/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Astrocytes, the most abundant glial cell type in the brain, play crucial roles in maintaining homeostasis within the central nervous system (CNS). Impairment or abnormalities of typical astrocyte functions in the CNS serve as a causative or contributing factor in numerous neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Currently, disease-modeling and drug-screening approaches, primarily focused on human astrocytes, rely on human pluripotent stem cell (hPSC)-derived astrocytes. However, it is important to acknowledge that these hPSC-derived astrocytes exhibit notable differences across studies and when compared to their in vivo counterparts. These differences may potentially compromise translational outcomes if not carefully accounted for. This review aims to explore state-of-the-art in vitro models of human astrocyte development, focusing on the developmental processes, functional maturity, and technical aspects of various hPSC-derived astrocyte differentiation protocols. Additionally, it summarizes their successful application in modeling neurological disorders. The discussion extends to recent advancements in the large-scale production of human astrocytes and their application in developing high-throughput assays conducive to therapeutic drug discovery.
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Astrocitos , Diferenciación Celular , Enfermedades del Sistema Nervioso , Células Madre Pluripotentes , Humanos , Astrocitos/metabolismo , Astrocitos/citología , Enfermedades del Sistema Nervioso/patología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Investigación Biomédica Traslacional , AnimalesRESUMEN
Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which are long-lived, non-dividing and highly polarized with specialized compartments such as axons and dendrites with distinct architecture, cargo, and turnover requirements. In recent years, there has been a growing appreciation for the role played by axonal lysosome transport in regulating neuronal development, its maintenance and functioning. Perturbations to optimal axonal lysosome abundance leading to either strong accumulations or dearth of lysosomes are both linked to altered neuronal health and functioning. In this review we highlight how two critical regulators of axonal lysosome transport and abundance, the small GTPase Arl8 and the adaptor protein JIP3, aid in maintaining axonal lysosome homeostasis and how alterations to their levels and activity could contribute to neurodevelopmental and neurodegenerative diseases.
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Transporte Axonal , Lisosomas , Humanos , Lisosomas/metabolismo , Animales , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Axones/metabolismoRESUMEN
IMPORTANCE: Although the role of bovine coronavirus (BCoV) in calf diarrhea and respiratory disorders is well documented, its contribution to neurological diseases is unclear. OBJECTIVE: This study conducted virological investigations of calves showing diarrhea and respiratory and neurological signs. METHODS: An outbreak of diarrhea, respiratory, and neurological disorders occurred among the 12 calves in July 2022 in Istanbul, Türkiye. Two of these calves exhibited neurological signs and died a few days after the appearance of symptoms. One of these calves was necropsied and analyzed using molecular and histopathological tests. RESULTS: BCoV RNA was detected in the brain, lung, spleen, liver, and intestine of the calf that had neurological signs by real-time reverse transcription polymerase chain reaction. Immunostaining was also observed in the intestine and brain. A 622 bp S1 gene product was noted on gel electrophoresis only in the brain. Phylogenetic analysis indicated that the BCoV detected in this study had a high proximity to the BCoV strain GIb with 99.19% nucleotide sequence homology to the strains detected in Poland, Israel, Türkiye, and France. No distinct genetic lineages were observed when the brain isolate was compared with the respiratory and enteric strains reported to GenBank. In addition, the highest identity (98,72%) was obtained with the HECV 4408 and L07748 strains of human coronaviruses. CONCLUSIONS AND RELEVANCE: The strain detected in a calf brain belongs to the GIb-European lineage and shares high sequence homology with BCoV strains detected in Europe and Israel. In addition, the similarity between the human coronaviruses (4408 and L07748) raises questions about the zoonotic potential of the strains detected in this study.
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Encéfalo , Enfermedades de los Bovinos , Infecciones por Coronavirus , Coronavirus Bovino , Filogenia , Animales , Bovinos , Coronavirus Bovino/genética , Coronavirus Bovino/aislamiento & purificación , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/patología , Enfermedades de los Bovinos/virología , Enfermedades de los Bovinos/patología , Encéfalo/virología , Encéfalo/patología , Turquía/epidemiología , Brotes de Enfermedades/veterinaria , Neumonía Viral/veterinaria , Neumonía Viral/virología , Neumonía Viral/patología , Enfermedades del Sistema Nervioso/veterinaria , Enfermedades del Sistema Nervioso/virología , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.1 explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain.
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Modelos Animales de Enfermedad , Macaca mulatta , Enfermedades del Sistema Nervioso , Caracteres Sexuales , Animales , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/fisiopatología , Humanos , Femenino , MasculinoRESUMEN
The human body is commonly exposed to bisphenol A (BPA), which is widely used in consumer and industrial products. BPA is an endocrine-disrupting chemical that has adverse effects on human health. In particular, many studies have shown that BPA can cause various neurological disorders by affecting brain development and neural function during prenatal, infancy, childhood, and adulthood exposure. In this review, we discussed the correlation between BPA and neurological disorders based on molecular cell biology, neurophysiology, and behavioral studies of the effects of BPA on brain development and function. Recent studies, both animal and epidemiological, strongly indicate that BPA significantly impacts brain development and function. It hinders neural processes, such as proliferation, migration, and differentiation during development, affecting synaptic formation and activity. As a result, BPA is implicated in neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia.
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Compuestos de Bencidrilo , Enfermedades del Sistema Nervioso , Fenoles , Humanos , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/toxicidad , Fenoles/toxicidad , Fenoles/efectos adversos , Animales , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/patología , Disruptores Endocrinos/efectos adversos , Disruptores Endocrinos/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/patologíaRESUMEN
Copper is a trace element required by the organism, but once the level of copper exceeds the threshold, it becomes toxic and even causes death. The underlying mechanisms of copper-induced death are inconclusive, with different studies showing different opinions on the mechanism of copper-induced death. Multiple investigations have shown that copper induces oxidative stress, endoplasmic reticulum stress, nucleolar stress, and proteasome inhibition, all of which can result in cell death. The latest research elucidates a copper-dependent death and denominates it as cuproptosis. Cuproptosis takes place through the combination of copper and lipoylated proteins of the tricarboxylic acid cycle, triggering agglomeration of lipoylated proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress and ultimately death. Given the toxicity and necessity of copper, abnormal levels of copper lead to diseases such as neurological diseases and cancer. The development of cancer has a high demand for copper, neurological diseases involve the change of copper contents and the binding of copper to proteins. There is a close relationship between these two kinds of diseases and copper. Here, we summarize the mechanisms of copper-related death, and the association between copper and diseases, to better figure out the influence of copper in cell death and diseases, thus advancing the clinical remedy of these diseases.
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Cobre , Neoplasias , Humanos , Cobre/metabolismo , Animales , Neoplasias/metabolismo , Neoplasias/patología , Estrés Oxidativo , Estrés del Retículo Endoplásmico , Muerte Celular , Apoptosis , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patologíaRESUMEN
PURPOSE: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was -3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (P = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.
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Genotipo , Cinesinas , Mutación Missense , Fenotipo , Humanos , Cinesinas/genética , Masculino , Femenino , Mutación Missense/genética , Niño , Adolescente , Adulto , Preescolar , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/fisiopatología , Adulto Joven , Persona de Mediana Edad , Estudios Longitudinales , Lactante , Convulsiones/genética , Convulsiones/fisiopatología , ElectroencefalografíaRESUMEN
Brain organoids hold great potential for modeling human brain development and pathogenesis. They recapitulate certain aspects of the transcriptional trajectory, cellular diversity, tissue architecture and functions of the developing brain. In this review, we explore the engineering strategies to control the molecular-, cellular- and tissue-level inputs to achieve high-fidelity brain organoids. We review the application of brain organoids in neural disorder modeling and emerging bioengineering methods to improve data collection and feature extraction at multiscale. The integration of multiscale engineering strategies and analytical methods has significant potential to advance insight into neurological disorders and accelerate drug development.
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Encéfalo , Organoides , Humanos , Encéfalo/metabolismo , Encéfalo/citología , Animales , Modelos Biológicos , Enfermedades del Sistema Nervioso/patología , Ingeniería de Tejidos/métodos , Bioingeniería/métodosRESUMEN
RATIONALE: White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most prevalent type, primarily associated with advanced age and cerebrovascular risk factors. Conversely, immunogenic WMLs, typified by multiple sclerosis (MS), are more frequently observed in younger patients. It is crucial to distinguish between these 2 etiologies. Furthermore, in cases where multiple individuals exhibit WMLs within 1 family, genetic testing may offer a significant diagnostic perspective. PATIENT CONCERNS: A 25-year-old male presented to the Department of Neurology with recurrent headaches. He was healthy previously and the neurological examination was negative. Brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensity lesions surrounding the ventricles and subcortical regions on T2-weighted and T2 fluid-attenuated inversion recovery images, mimicking immunogenic disease-MS. DIAGNOSES: The patient was diagnosed with a patent foramen ovale, which could explain his headache syndrome. Genetic testing unveiled a previously unidentified missense mutation in the SERPINC1 gene in the patient and his father. The specific abnormal laboratory finding was a reduction in antithrombin III activity, and the decrease may serve as the underlying cause for the presence of multiple intracranial WMLs observed in both the patient and his father. INTERVENTIONS: The patient received percutaneous patent foramen ovale closure surgery and took antiplatelet drug recommended by cardiologists and was followed up for 1 month and 6 months after operation. OUTCOMES: While the lesions on MRI remain unchanging during follow-up, the patient reported a significant relief in headaches compared to the initial presentation. LESSONS: This case introduces a novel perspective on the etiology of cerebral WMLs, suggesting that hereditary antithrombin deficiency (ATD) could contribute to altered blood composition and may serve as an underlying cause in certain individuals with asymptomatic WMLs.
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Deficiencia de Antitrombina III , Foramen Oval Permeable , Esclerosis Múltiple , Enfermedades del Sistema Nervioso , Enfermedades Vasculares , Sustancia Blanca , Masculino , Humanos , Adulto , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Foramen Oval Permeable/patología , Antitrombina III/genética , Deficiencia de Antitrombina III/complicaciones , Deficiencia de Antitrombina III/genética , Deficiencia de Antitrombina III/patología , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Enfermedades Vasculares/patología , Enfermedades del Sistema Nervioso/patología , Esclerosis Múltiple/diagnóstico , Cefalea , Mutación , AntitrombinasRESUMEN
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.
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Exosomas , Exosomas/metabolismo , Humanos , Animales , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Innate lymphocytes, including microglial cells, astrocytes, and oligodendrocytes, play a crucial role in initiating neuroinflammatory reactions inside the central nervous system (CNS). The prime focus of this paper is on the involvement and interplay of neurons and glial cells in neurological disorders such as Alzheimer's Disease (AD), Autism Spectrum Disorder (ASD), epilepsy, and multiple sclerosis (MS). In this review, we explore the specific contributions of microglia and astrocytes and analyzes multiple pathways implicated in neuroinflammation and disturbances in excitatory and inhibitory processes. Firstly, we elucidate the mechanisms through which toxic protein accumulation in AD results in synaptic dysfunction and deregulation of the immune system and examines the roles of microglia, astrocytes, and hereditary factors in the pathogenesis of the disease. Secondly, we focus on ASD and the involvement of glial cells in the development of the nervous system and the formation of connections between neurons and investigates the genetic connections associated with these processes. Lastly, we also address the participation of glial cells in epilepsy and MS, providing insights into their pivotal functions in both conditions. We also tried to give an overview of seven different pathways like toll-like receptor signalling pathway, MyD88-dependent and independent pathway, etc and its relevance in the context with these neurological disorders. In this review, we also explore the role of activated glial cells in AD, ASD, epilepsy, and MS which lead to neuroinflammation. Even we focus on excitatory and inhibitory imbalance in all four neurological disorders as imbalance affect the proper functioning of neuronal circuits. Finally, this review concludes that there is necessity for additional investigation on glial cells and their involvement in neurological illnesses.
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Enfermedades del Sistema Nervioso , Neuroglía , Neuronas , Animales , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Astrocitos/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Comunicación Celular , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/fisiopatología , Microglía/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/fisiopatología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Neuroglía/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/metabolismo , Transducción de SeñalRESUMEN
Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as HOTAIR. HOTAIR epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, HOTAIR elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of HOTAIR in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of HOTAIR in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of HOTAIR in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of HOTAIR in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating HOTAIR in the pathogeneses of gliomas and other brain cancers. Implications of HOTAIR serving as a suitable therapeutic target in neuropathologies are also discussed.
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ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Animales , Pronóstico , Epigénesis Genética , Biomarcadores , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/terapia , Enfermedades del Sistema Nervioso/patología , Glioma/genética , Glioma/patología , Glioma/terapia , Glioma/metabolismoRESUMEN
BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.
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Enfermedades de los Caballos , Linaje , Animales , Caballos , Enfermedades de los Caballos/genética , Enfermedades de los Caballos/patología , Masculino , Femenino , América del Norte , Ataxias Espinocerebelosas/veterinaria , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Enfermedades del Sistema Nervioso/veterinaria , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, contributes to neurological pathologies in nearly 30% of patients, extending beyond respiratory symptoms. These manifestations encompass disorders of both the peripheral and central nervous systems, causing among others cerebrovascular issues and psychiatric manifestations during the acute and/or post-acute infection phases. Despite ongoing research, uncertainties persist about the precise mechanism the virus uses to infiltrate the central nervous system and the involved entry portals. This review discusses the potential entry routes, including hematogenous and anterograde transport. Furthermore, we explore variations in neurotropism, neurovirulence, and neurological manifestations among pandemic-associated variants of concern. In conclusion, SARS-CoV-2 can infect numerous cells within the peripheral and central nervous system, provoke inflammatory responses, and induce neuropathological changes.
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COVID-19 , SARS-CoV-2 , Tropismo Viral , Humanos , COVID-19/virología , COVID-19/patología , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Sistema Nervioso Central/virología , Sistema Nervioso Central/patología , Animales , Enfermedades del Sistema Nervioso/virología , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/fisiopatología , Internalización del VirusRESUMEN
The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable to genetic engineering, and can be differentiated into most somatic cell types. iPSCs have been widely applied to model human development and diseases, perform drug screening, and develop cell therapies. In this review, we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications. We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs. We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency. Subsequently, we discuss various iPSC-based cellular models, from mono-cultures of a single cell type to complex three-dimensional organoids, and how these models can be applied to elucidate the mechanisms of human development and diseases. We use examples of neurological disorders, coronavirus disease 2019 (COVID-19), and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells. We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies. Finally, we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.
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COVID-19 , Reprogramación Celular , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/citología , Reprogramación Celular/genética , SARS-CoV-2/genética , Diferenciación Celular/genética , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patología , Medicina Regenerativa , Enfermedades del Sistema Nervioso/terapia , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.