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International Journal of Molecular... Feb 2019Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons,... (Review)
Review
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca signals. We discuss the molecular mechanisms underlying aberrant Ca signals in reactive astrocytes and the functional significance of aberrant Ca signals in neurological disorders.
Topics: Animals; Astrocytes; Calcium; Calcium Signaling; Humans; Mice; Nervous System Diseases; Rats
PubMed: 30823575
DOI: 10.3390/ijms20040996 -
International Journal of Molecular... Aug 2022Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of... (Review)
Review
Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet-Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus-Merzbacher disease), transcriptional deregulation diseases (Mowat-Wilson disease, Pitt-Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction.
Topics: Animals; Bardet-Biedl Syndrome; Cerebellum; Comorbidity; Neuromyelitis Optica; Pathology, Molecular
PubMed: 36077104
DOI: 10.3390/ijms23179707 -
Neurotherapeutics : the Journal of the... Oct 2010Alexander disease is a rare and generally fatal disorder of the CNS, originally classified among the leukodystrophies because of the prominent myelin deficits found in... (Review)
Review
Alexander disease is a rare and generally fatal disorder of the CNS, originally classified among the leukodystrophies because of the prominent myelin deficits found in young patients. The most common form of this disease affects infants, who often have profound mental retardation and a variety of developmental delays, but later onset forms also occur, sometimes with little or no white matter pathology at all. The pathological hallmark of Alexander disease is the inclusion body, known as Rosenthal fiber, within the cell bodies and processes of astrocytes. Recent genetic studies identified heterozygous missense mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes, as the cause of nearly all cases of Alexander disease. These studies have transformed our view of this disorder and opened new directions for investigation and clinical practice, particularly with respect to diagnosis. Mechanisms by which expression of mutant forms of glial fibrillary acidic protein (GFAP) lead to the pleiotropic manifestations of disease (afflicting cell types beyond the ones expressing the mutant gene) are slowly coming into focus. Ideas are beginning to emerge that suggest several compelling therapeutic targets for interventions that might slow or arrest the evolution of the disease. This review will outline the rationale for pursuing these strategies, and highlight some of the critical issues that must be addressed in the planning of future clinical trials.
Topics: Alexander Disease; Amino Acid Transport System X-AG; Animals; Astrocytes; Glial Fibrillary Acidic Protein; Humans; Receptors, Neurotensin; alpha-Crystallins
PubMed: 20880512
DOI: 10.1016/j.nurt.2010.05.013 -
International Journal of Molecular... Oct 2023The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly... (Review)
Review
The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly affect the development and progression of various immune-mediated diseases affecting both the digestive tract and the central nervous system (CNS). This complex interplay between the microbiota, the gut, and the CNS is referred to as the gut-brain axis. The role of the gut microbiota in the pathogenesis of neurodegenerative diseases has gained increasing attention in recent years, and evidence suggests that gut dysbiosis may contribute to disease development and progression. Clinical studies have shown alterations in the composition of the gut microbiota in multiple sclerosis patients, with a decrease in beneficial bacteria and an increase in pro-inflammatory bacteria. Furthermore, changes within the microbial community have been linked to the pathogenesis of Parkinson's disease and Alzheimer's disease. Microbiota-gut-brain communication can impact neurodegenerative diseases through various mechanisms, including the regulation of immune function, the production of microbial metabolites, as well as modulation of host-derived soluble factors. This review describes the current literature on the gut-brain axis and highlights novel communication systems that allow cross-talk between the gut microbiota and the host that might influence the pathogenesis of neuroinflammation and neurodegeneration.
Topics: Humans; Neuroinflammatory Diseases; Brain; Microbiota; Central Nervous System; Neurodegenerative Diseases; Dysbiosis
PubMed: 37834373
DOI: 10.3390/ijms241914925 -
Balkan Journal of Medical Genetics :... Dec 2019Alexander disease (AxD) is a rare autosomal dominant leukodystrophy with three clinical subtypes: infantile, juvenile and adult. Forms differ by age of symptoms...
Alexander disease (AxD) is a rare autosomal dominant leukodystrophy with three clinical subtypes: infantile, juvenile and adult. Forms differ by age of symptoms occurrence and the clinical presentation. Although recent data suggest considering only two subtypes: type I (infantile onset with lesions extending to the cerebral hemispheres); type II (adult onset with primary involvement of subtentorial structures). Dominant mutations in the glial fibrillary acidic protein () gene in AxD cause dysfunction of astrocytes (a type III intermediate filament). The authors discuss the clinical picture of a boy with infantile form of AxD confirmed by the presence of heterozygous mutation c.236G>A in the gene and without striking symptoms such as macrocephaly and with exceptional late-onset epileptic spasms with hypsarrhyth- mia on electroencephalogram (EEG).
PubMed: 31942421
DOI: 10.2478/bjmg-2019-0017 -
JFMS Open Reports 2019A 14-year-old neutered female Burmese cat was referred for investigation of a caudal oropharyngeal mass. CT showed a thin walled cyst-like structure filling and...
CASE SUMMARY
A 14-year-old neutered female Burmese cat was referred for investigation of a caudal oropharyngeal mass. CT showed a thin walled cyst-like structure filling and expanding from the right tympanic bulla. Histopathology showed fragments of mildly dysplastic squamous epithelium and aggregates of keratin. These findings were considered consistent with a diagnosis of cholesteatoma.
RELEVANCE AND NOVEL INFORMATION
To the best of our knowledge, this is the first reported case of a cholesteatoma in a cat. Cholesteatoma should be considered a differential diagnosis for cats presenting with a caudal oropharyngeal mass, a history of chronic ear disease or a history of previous, surgically managed middle ear disease. Advanced imaging and biopsies should be considered important in the diagnosis of these lesions.
PubMed: 31205737
DOI: 10.1177/2055116919848086 -
Acta Neuropathologica Communications Jul 2016Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic...
Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.
Topics: Adult; Aged; Alexander Disease; Astrocytes; Cell Culture Techniques; Cells, Cultured; Child; Cytokines; Electrochemical Techniques; Female; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Humans; Immunoblotting; Induced Pluripotent Stem Cells; Male; Microarray Analysis; Microscopy, Electron, Transmission; Middle Aged; Protein Aggregation, Pathological
PubMed: 27402089
DOI: 10.1186/s40478-016-0337-0 -
P & T : a Peer-reviewed Journal For... Feb 2018We review key sessions on Hodgkin's lymphoma, diffuse large B-cell lymphoma, thromboembolism, hemophilia, sickle cell disease, and chronic lymphocytic leukemia.
We review key sessions on Hodgkin's lymphoma, diffuse large B-cell lymphoma, thromboembolism, hemophilia, sickle cell disease, and chronic lymphocytic leukemia.
PubMed: 29386868
DOI: No ID Found -
Herz Mar 2024Cardiovascular diseases (CVD) are closely linked to protein homeostasis (proteostasis) and its failure. Beside genetic mutations that impair cardiac protein quality... (Review)
Review
Cardiovascular diseases (CVD) are closely linked to protein homeostasis (proteostasis) and its failure. Beside genetic mutations that impair cardiac protein quality control, obesity is a strong risk factor for heart disease. In obesity, adipose tissue becomes dysfunctional and impacts heart function and CVD progression by releasing cytokines that contribute to systemic insulin resistance and cardiovascular dysfunction. In addition, chronic inflammation and lipotoxicity compromise endoplasmic reticulum (ER) function, eliciting stress responses that overwhelm protein quality control beyond its capacity. Impairment of proteostasis-including dysfunction of the ubiquitin-proteasome system (UPS), autophagy, and the depletion of chaperones-is intricately linked to cardiomyocyte dysfunction. Interventions targeting UPS and autophagy pathways are new potential strategies for re-establishing protein homeostasis and improving heart function. Additionally, lifestyle modifications such as dietary interventions and exercise have been shown to promote cardiac proteostasis and overall metabolic health. The pursuit of future research dedicated to proteostasis and protein quality control represents a pioneering approach for enhancing cardiac health and addressing the complexities of obesity-related cardiac dysfunction.
Topics: Humans; Proteostasis; Cardiovascular Diseases; Myocytes, Cardiac; Heart Diseases; Proteasome Endopeptidase Complex; Obesity
PubMed: 38329532
DOI: 10.1007/s00059-024-05233-6 -
Frontiers in Neurology 2022Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic...
Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox-Gastaut syndrome and myoclonic-astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.
PubMed: 36601294
DOI: 10.3389/fneur.2022.1002527