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BMB Reports Nov 202014-3-3 proteins are mostly expressed in the brain and are closely involved in numerous brain functions and various brain disorders. Among the isotypes of the 14-3-3... (Review)
Review
14-3-3 proteins are mostly expressed in the brain and are closely involved in numerous brain functions and various brain disorders. Among the isotypes of the 14-3-3 proteins, 14-3-3γ is mainly expressed in neurons and is highly produced during brain development, which could indicate that it has a significance in neural development. Furthermore, the distinctive levels of temporally and locally regulated 14-3-3γ expression in various brain disorders suggest that it could play a substantial role in brain plasticity of the diseased states. In this review, we introduce the various brain disorders reported to be involved with 14-3-3γ, and summarize the changes of 14-3-3γ expression in each brain disease. We also discuss the potential of 14-3-3γ for treatment and the importance of research on specific 14-3-3 isotypes for an effective therapeutic approach. [BMB Reports 2020; 53(10): 500-511].
Topics: 14-3-3 Proteins; Animals; Brain; Brain Diseases; Humans; Neurogenesis; Neurons; Phosphorylation; Protein Binding
PubMed: 32958119
DOI: 10.5483/BMBRep.2020.53.10.158 -
Biogerontology Apr 2015Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is... (Review)
Review
Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.
Topics: Aging; Animals; Brain; Brain Diseases; Cell Communication; Extracellular Vesicles; Humans; Models, Biological
PubMed: 24973266
DOI: 10.1007/s10522-014-9510-7 -
NeuroImage Oct 2023Observational studies consistently disclose brain imaging-derived phenotypes (IDPs) as critical markers for early diagnosis of both brain disorders and cardiovascular...
Observational studies consistently disclose brain imaging-derived phenotypes (IDPs) as critical markers for early diagnosis of both brain disorders and cardiovascular diseases. However, it remains unclear about the shared genetic landscape between brain IDPs and the risk of brain disorders and cardiovascular diseases, restricting the applications of potential diagnostic techniques through brain IDPs. Here, we reported genetic correlations and putative causal relationships between 921 brain IDPs, 20 brain disorders and six cardiovascular diseases by leveraging their large-scale genome-wide association study (GWAS) summary statistics. Applications of Mendelian randomization (MR) identified significant putative causal effects of multiple region-specific brain IDPs in relation to the increased risks for amyotrophic lateral sclerosis (ALS), major depressive disorder (MDD), autism spectrum disorder (ASD) and schizophrenia (SCZ). We also found brain IDPs specifically from temporal lobe as a putatively causal consequence of hypertension. The genome-wide colocalization analysis identified three genomic regions in which MDD, ASD and SCZ colocalized with the brain IDPs, and two novel SNPs to be associated with ASD, SCZ, and multiple brain IDPs. Furthermore, we identified a list of candidate genes involved in the shared genetics underlying pairs of brain IDPs and MDD, ASD, SCZ, ALS and hypertension. Our results provide novel insights into the genetic relationships between brain disorders and cardiovascular diseases and brain IDP, which may server as clues for using brain IDPs to predict risks of diseases.
Topics: Humans; Depressive Disorder, Major; Cardiovascular Diseases; Genome-Wide Association Study; Autism Spectrum Disorder; Amyotrophic Lateral Sclerosis; Mendelian Randomization Analysis; Phenotype; Brain Diseases; Hypertension; Neuroimaging
PubMed: 37579999
DOI: 10.1016/j.neuroimage.2023.120325 -
Dialogues in Clinical Neuroscience Mar 2013The increased risk for neurodegenerative and neuropsychiatric disorders associated with extended lifespan has long suggested mechanistic links between chronological age... (Review)
Review
The increased risk for neurodegenerative and neuropsychiatric disorders associated with extended lifespan has long suggested mechanistic links between chronological age and brain-related disorders, including depression, Recent characterizations of age-dependent gene expression changes now show that aging of the human brain engages a specific set of biological pathways along a continuous lifelong trajectory, and that the same genes that are associated with normal brain aging are also frequently and similarly implicated in depression and other brain-related disorders. These correlative observations suggest a model of age-by-disease molecular interactions, in which brain aging promotes biological changes associated with diseases, and additional environmental factors and genetic variability contribute to defining disease risk or resiliency trajectories. Here we review the characteristic features of brain aging in terms of changes in gene function over time, and then focus on evidence supporting accelerated molecular aging in depression. This proposed age-by-disease biological interaction model addresses the current gap in research between "normal" brain aging and its connection to late-life diseases. The implications of this model are profound, as it provides an investigational framework for identifying critical moderating factors, outlines opportunities for early interventions or preventions, and may form the basis for a dimensional definition of diseases that goes beyond the current categorical system.
Topics: Aging; Brain; Brain Diseases; Depression; Gene Expression; Humans; Nerve Tissue Proteins
PubMed: 23576889
DOI: 10.31887/DCNS.2013.15.1/esibille -
Journal of Veterinary Internal Medicine 2024Polioencephalopathies secondary to inborn errors of metabolism have been described in dogs, but few genetically characterized.
BACKGROUND
Polioencephalopathies secondary to inborn errors of metabolism have been described in dogs, but few genetically characterized.
OBJECTIVES
Clinically and genetically characterize polioencephalopathy in a family of Eurasier dogs.
ANIMALS
Three Eurasier dogs (littermates) presented with early onset movement disorders (9 weeks in 2, 4-6 months in 1). Progressive gait abnormalities were detected in 2 of the dogs, persistent divergent strabismus in 1, whereas consciousness and behavior remained intact in all dogs. One dog was euthanized at 25 months.
METHODS
Video footage was assessed in all dogs, and Dogs 1 and 2 had examinations and investigations performed. Whole genome sequencing of Dog 1 and further genetic analyses in the family were performed. A cohort of 115 Eurasier controls was genotyped for specific variants.
RESULTS
Episodes were characterized by generalized ataxia, as well as a hypermetric thoracic limb gait, dystonia, and irregular flexion and extension movements of the thoracic limbs. Magnetic resonance imaging of the brain in Dogs 1 and 2 identified symmetrical, bilateral T2 and fluid attenuated inversion recovery hyperintense, T1 hypo to isointense, nonenhancing lesions of the caudate nucleus, lateral and medial geniculate nuclei, thalamus, hippocampus, rostral colliculus and mild generalized brain atrophy. Genetic analyses identified a homozygous mitochondrial trans-2-enoyl-CoA reductase (MECR) missense variant in all 3 dogs, and a homozygous autophagy-related gene 4D (ATG4D) missense variant in Dogs 1 and 2.
CONCLUSIONS AND CLINICAL IMPORTANCE
We describe a presumed hereditary and progressive polioencephalopathy in a family of Eurasier dogs. Further research is needed to establish the role of the MECR gene in dogs and the pathogenic effects of the detected variants.
Topics: Humans; Dogs; Animals; Brain Diseases; Brain; Genotype; Mutation, Missense; Homozygote; Dog Diseases
PubMed: 38041431
DOI: 10.1111/jvim.16945 -
Lancet (London, England) Sep 2012Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and... (Review)
Review
Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and investigation in view of their adverse effect on the course and quality of life. In this report we define the specific psychiatric, cognitive, and social comorbidities of paediatric and adult epilepsy, their epidemiology, and real life effects; examine the relation between epilepsy syndromes and the risk of neurobehavioural comorbidities; address the lifespan effect of epilepsy on brain neurodevelopment and brain ageing and the risk of neurobehavioural comorbidities; consider the overarching effect of broader brain disorders on both epilepsy and neurobehavioural comorbidities; examine directions of causality and the contribution of selected epilepsy-related characteristics; and outline clinic-friendly screening approaches for these problems and recommended pharmacological, behavioural, and educational interventions.
Topics: Aging; Brain; Brain Diseases; Cognition Disorders; Comorbidity; Epilepsy; Humans; Mental Disorders
PubMed: 23021287
DOI: 10.1016/S0140-6736(12)61455-X -
The Journal of Nutrition Oct 2020Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are... (Review)
Review
Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are not well described yet, glutaric aciduria type I (GA1) and antiquitin (2-aminoadipic-6-semialdehyde dehydrogenase) deficiency represent the most well-characterized diseases. GA1 is an autosomal recessive disorder due to a deficiency of glutaryl-CoA dehydrogenase. Untreated patients exhibit early onset macrocephaly and may present a neurological deterioration with regression and movement disorder at the time of a presumably "benign" infection most often during the first year of life. This is associated with a characteristic neuroimaging pattern with frontotemporal atrophy and striatal injuries. Diagnosis relies on the identification of glutaric and 3-hydroxyglutaric acid in urine along with plasma glutarylcarnitine. Treatment consists of a low-lysine diet aiming at reducing the putatively neurotoxic glutaric and 3-hydroxyglutaric acids. Additional therapeutic measures include administration of l-carnitine associated with emergency measures at the time of intercurrent illnesses aiming at preventing brain injury. Early treated (ideally through newborn screening) patients exhibit a favorable long-term neurocognitive outcome, whereas late-treated or untreated patients may present severe neurocognitive irreversible disabilities. Antiquitin deficiency is the most common form of pyridoxine-dependent epilepsy. α-Aminoadipic acid semialdehyde (AASA) and Δ-1-piperideine-6-carboxylate (P6C) accumulate proximal to the enzymatic block. P6C forms a complex with pyridoxal phosphate (PLP), a key vitamer of pyridoxine, thereby reducing PLP bioavailability and subsequently causing epilepsy. Urinary AASA is a biomarker of antiquitin deficiency. Despite seizure control, only 25% of the pyridoxine-treated patients show normal neurodevelopment. Low-lysine diet and arginine supplementation are proposed in some patients with decrease of AASA, but the impact on neurodevelopment is unclear. In summary, GA1 and antiquitin deficiency are the 2 main human defects of lysine catabolism. Both include neurological impairment. Lysine dietary restriction is a key therapy for GA1, whereas its benefits in antiquitin deficiency appear less clear.
Topics: 2-Aminoadipic Acid; Aldehyde Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Arginine; Brain; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Carnitine; Epilepsy; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Lysine; Metabolic Diseases; Pyridoxal Phosphate; Pyridoxine
PubMed: 33000154
DOI: 10.1093/jn/nxaa112 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Dec 2017Epilepsy is a common chronic brain disorder with multiple causes, and now autoimmune factors are believed to be an independent cause for epilepsy. Accumulating data... (Review)
Review
Epilepsy is a common chronic brain disorder with multiple causes, and now autoimmune factors are believed to be an independent cause for epilepsy. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Moreover, systemic autoimmune diseases and epilepsy co-occur frequently. Neural specific autoantibodies can also mediate the process of seizures through different pathways. The diagnosis of autoimmune epilepsy is based on frequency of antiepileptic drug-resistant seizures, the presence of neural specific autoantibodies, inflammatory changes in serum or spinal fluid or on magneticresonanceimaging, the change in electroencephalogram, a personal or family history of autoimmunity. Once autoimmune epilepsy is diagnosed, the immunotherapy is required. Early immunotherapy is crucial for improving the prognosis of the patients.
Topics: Anticonvulsants; Autoantibodies; Autoimmune Diseases of the Nervous System; Brain Diseases; Drug Resistance; Electroencephalography; Epilepsy; Humans; Immunotherapy
PubMed: 29317588
DOI: 10.11817/j.issn.1672-7347.2017.12.015 -
Current Neuropharmacology 2017Cannabis is the most widely used illicit drug in the world and there is growing concern about the mental health effects of cannabis use. These concerns are at least... (Review)
Review
BACKGROUND
Cannabis is the most widely used illicit drug in the world and there is growing concern about the mental health effects of cannabis use. These concerns are at least partly due to the strong increase in recreational and medical cannabis use and the rise in tetrahydrocannabinol (THC) levels. Cannabis is widely used to self-medicate by older people and people with brain disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), bipolar disorder, and schizophrenia.
OBJECTIVE
This review provides an overview of the perceived benefits and adverse mental health effects of cannabis use in people with ALS, MS, AD, PD, bipolar disorder, and schizophrenia.
RESULTS
The reviewed studies indicate that cannabis use diminishes some symptoms associated with these disorders. Cannabis use decreases pain and spasticity in people with MS, decreases tremor, rigidity, and pain in people with PD, and improves the quality of life of ALS patients by improving appetite, and decreasing pain and spasticity. Cannabis use is more common among people with schizophrenia than healthy controls. Cannabis use is a risk factor for schizophrenia which increases positive symptoms in schizophrenia patients and diminishes negative symptoms. Cannabis use worsens bipolar disorder and there is no evidence that bipolar patients derive any benefit from cannabis. In late stage Alzheimer's patients, cannabis products may improve food intake, sleep quality, and diminish agitation.
CONCLUSION
Cannabis use diminishes some of the adverse effects of neurological and psychiatric disorders. However, chronic cannabis use may lead to cognitive impairments and dependence.
Topics: Animals; Brain Diseases; Chronic Disease; Humans; Medical Marijuana; Mental Disorders; Substance-Related Disorders
PubMed: 27804883
DOI: 10.2174/1570159X14666161101095325 -
Dialogues in Clinical Neuroscience 2007The neuropsychiatric manifestations of neurodegenerative diseases are closely linked to neurocircuitry defects. Frontal-subcortical circuits, in particular, are effector... (Review)
Review
The neuropsychiatric manifestations of neurodegenerative diseases are closely linked to neurocircuitry defects. Frontal-subcortical circuits, in particular, are effector mechanisms that allow the organism to act on its environment. In this paper, we present the three main frontal-subcortical circuits: the dorsolateral prefrontal circuit allows the organization of information to facilitate a response; the anterior cingulate circuit is required for motivated behavior; and the orbitofrontal circuit allows the integration of limbic and emotional information into behavioral responses. Impaired executive functions, apathy, and impulsivity are hallmarks of frontal-subcortical circuit dysfunction. A variety of other neuropsychiatric disorders, such as Tourette's syndrome, Huntington's disease, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, schizophrenia, and mood disorders may result from disturbances that have a direct or indirect impact on the integrity or functioning of these loops.
Topics: Animals; Brain Diseases; Emotions; Gyrus Cinguli; Humans; Limbic System; Mental Disorders; Mood Disorders; Neural Pathways; Prefrontal Cortex
PubMed: 17726913
DOI: 10.31887/DCNS.2007.9.2/rbonelli