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1.
Adv Exp Med Biol ; 1131: 699-718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646531

RESUMO

Calcium exchanges and homeostasis are finely regulated between cellular organelles and in response to physiological signals. Besides ionophores, including voltage-gated Ca2+ channels, ionotropic neurotransmitter receptors, or Store-operated Ca2+ entry, activity of regulatory intracellular proteins finely tune Calcium homeostasis. One of the most intriguing, by its unique nature but also most promising by the therapeutic opportunities it bears, is the sigma-1 receptor (Sig-1R). The Sig-1R is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it interacts with several partners involved in ER stress response, or in Ca2+ exchange between the ER and mitochondria. Small molecules have been identified that specifically and selectively activate Sig-1R (Sig-1R agonists or positive modulators) at the cellular level and that also allow effective pharmacological actions in several pre-clinical models of pathologies. The present review will summarize the recent data on the mechanism of action of Sig-1R in regulating Ca2+ exchanges and protein interactions at MAMs and the ER. As MAMs alterations and ER stress now appear as a common track in most neurodegenerative diseases, the intracellular action of Sig-1R will be discussed in the context of the recently reported efficacy of Sig-1R drugs in pathologies like Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis.


Assuntos
Membrana Celular , Estresse do Retículo Endoplasmático , Doenças Neurodegenerativas , Receptores sigma , Membrana Celular/metabolismo , Membrana Celular/patologia , Humanos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Receptores sigma/metabolismo
2.
Adv Exp Med Biol ; 1131: 719-746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646532

RESUMO

It is generally accepted that interorganellar contacts are central to the control of cellular physiology. Virtually, any intracellular organelle can come into proximity with each other and, by establishing physical protein-mediated contacts within a selected fraction of the membrane surface, novel specific functions are acquired. Endoplasmic reticulum (ER) contacts with mitochondria are among the best studied and have a major role in Ca2+ and lipid transfer, signaling, and membrane dynamics.Their functional (and structural) diversity, their dynamic nature as well as the growing number of new players involved in the tethering concurred to make their monitoring difficult especially in living cells. This review focuses on the most established examples of tethers/modulators of the ER-mitochondria interface and on the roles of these contacts in health and disease by specifically dissecting how Ca2+ transfer occurs and how mishandling eventually leads to disease. Additional functions of the ER-mitochondria interface and an overview of the currently available methods to measure/quantify the ER-mitochondria interface will also be discussed.


Assuntos
Cálcio , Retículo Endoplasmático , Mitocôndrias , Doenças Neurodegenerativas , Cálcio/metabolismo , Sinalização do Cálcio , Retículo Endoplasmático/metabolismo , Humanos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transdução de Sinais
3.
Adv Exp Med Biol ; 1131: 681-697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646530

RESUMO

Neurons are long-lived post-mitotic cells that possess an elaborate system of endosomes and lysosomes (endolysosomes) for protein quality control. Relatively recently, endolysosomes were recognized to contain high concentrations (400-600 µM) of readily releasable calcium. The release of calcium from this acidic organelle store contributes to calcium-dependent processes of fundamental physiological importance to neurons including neurotransmitter release, membrane excitability, neurite outgrowth, synaptic remodeling, and cell viability. Pathologically, disturbances of endolysosome structure and/or function have been noted in a variety of neurodegenerative disorders including Alzheimer's disease (AD) and HIV-1 associated neurocognitive disorder (HAND). And, dysregulation of intracellular calcium has been implicated in the neuropathogenesis of these same neurological disorders. Thus, it is important to better understand mechanisms by which calcium is released from endolysosomes as well as the consequences of such release to inter-organellar signaling, physiological functions of neurons, and possible pathological consequences. In doing so, a path forward towards new therapeutic modalities might be facilitated.


Assuntos
Cálcio , Lisossomos , Doenças Neurodegenerativas , Neurônios , Cálcio/metabolismo , Sinalização do Cálcio , Endossomos/fisiologia , Humanos , Lisossomos/patologia , Lisossomos/fisiologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/fisiologia
4.
Adv Exp Med Biol ; 1203: 195-245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31811636

RESUMO

In recent years, cytoplasmic RNA granules, which are micron-sized membrane-less entities formed by phase separation, have progressively gained recognition as essential constituents of neuronal RNA metabolism. Stress granules form under adverse growth conditions in order to protect nontranslating mRNA, shift translation toward the production of prosurvival factors, as well as potentially serve as hubs for intracellular signaling. In contrast, processing bodies play a role in RNA degradation in both stressed and homeostatic conditions. Lastly, transport granules permit, as their name indicates, the transport of mRNA within neurons. All of these granule subtypes are required for proper neuronal function; thus, impairments in their regulation and/or composition are expected to be deleterious. Here, we review these cytoplasmic RNA granule subtypes and discuss how they have been implicated in some neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas , RNA Mensageiro , Grânulos Citoplasmáticos/metabolismo , Humanos , Doenças Neurodegenerativas/fisiopatologia , RNA Mensageiro/metabolismo
5.
Nat Med ; 25(12): 1822-1832, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806905

RESUMO

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.


Assuntos
Doença Crônica/epidemiologia , Inflamação/fisiopatologia , Longevidade/genética , Doenças Autoimunes/etiologia , Doenças Autoimunes/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/epidemiologia , Estilo de Vida , Longevidade/fisiologia , Neoplasias/etiologia , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco
6.
Adv Exp Med Biol ; 1206: 435-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31776997

RESUMO

Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy (CMA) was the first lysosomal process to be discovered by which intracellular components are selectively degraded. This process involves the recognition of the substrate, the unfolding and translocation of the substrate, and the degradation of the substrate. By degrading specific target proteins in a timely manner, CMA is involved in a variety of cellular activities. In the past few years, we have acquired a better understanding of how CMA is regulated. It has been reported that peroxide accumulation, aging and/or other pathological signals interfere with CMA function, which in turn induces neurodegenerative diseases, cancer, and other diseases. Combining results from the current research, we summarize the basic processes, regulatory mechanisms, and physiological functions of CMA and discuss its critical role in the development of diseases.


Assuntos
Autofagia , Chaperonas Moleculares , Humanos , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia
7.
Adv Exp Med Biol ; 1206: 509-525, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31777001

RESUMO

Autophagy is a conserved process that degrades intracellular components through lysosomes, thereby maintaining energy homeostasis and renewal of organelles. Mounting evidence indicates that autophagy plays a key role in aging and aging-related diseases. Enhanced autophagy can delay aging and prolong life span. The absence of autophagy leads to the accumulation of mutant and misfolded proteins in the cell, which is the basis for the emergence and development of neurodegenerative diseases and other aging-related diseases. It will be of importance to develop approaches to extend the lifespan and improve the health of elderly individuals through the modulation of autophagy.


Assuntos
Envelhecimento , Autofagia , Longevidade , Homeostase , Humanos , Lisossomos , Doenças Neurodegenerativas/fisiopatologia
8.
Mol Biol (Mosk) ; 53(5): 790-798, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661478

RESUMO

Recently, much attention has been drawn to unraveling the mechanisms of neurodegenerative and neuroinflammatory disease pathogenesis. A special role in the development of neuropathologies is assigned to the interaction of the nervous and the immune systems. Microglia are the cells of the immune system that function as resident macrophages of the central nervous system (CNS) and are involved in the development of CNS, as well as in homeostatic interactions. Impaired microglia can contribute to neuroinflammation and neurodegeneration. With the help of genome editing technologies, the main paradigms in the development and functions of microglia have been addressed. At the same time, an understanding of the mechanisms of regulation of microglia in normal and pathological conditions is necessary to create an effective therapy aimed at treating various neurological diseases. This review focuses on recent findings on the origin of microglia, its regulatory role in the central nervous system, as well as its contribution to the development of neuroinflammation.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiologia , Homeostase , Inflamação/patologia , Microglia/fisiologia , Doenças Neurodegenerativas/patologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Humanos , Inflamação/fisiopatologia , Microglia/citologia , Microglia/patologia , Doenças Neurodegenerativas/fisiopatologia
9.
Phys Chem Chem Phys ; 21(41): 22679-22694, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31595905

RESUMO

Peptide misfolding and aberrant assembly in membranous micro-environments have been associated with numerous neurodegenerative diseases. The biomolecular mechanisms and biophysical implications of these amyloid membrane interactions have been under extensive research and can assist in understanding disease pathogenesis and potential development of rational therapeutics. But, the complex nature and diversity of biomolecular interactions, structural transitions, and dependence on local environmental conditions have made accurate microscopic characterization challenging. In this review, using cases of Alzheimer's disease (amyloid-beta peptide), Parkinson's disease (alpha-synuclein peptide) and Huntington's disease (huntingtin protein), we illustrate existing challenges in experimental investigations and summarize recent relevant numerical simulation studies into amyloidogenic peptide-membrane interactions. In addition we project directions for future in silico studies and discuss shortcomings of current computational approaches.


Assuntos
Biologia Computacional , Lipídeos/química , Doenças Neurodegenerativas , Dobramento de Proteína , Proteínas Amiloidogênicas/metabolismo , Membrana Celular/metabolismo , Simulação por Computador , Humanos , Metabolismo dos Lipídeos , Doenças Neurodegenerativas/fisiopatologia , Peptídeos/metabolismo
10.
BMC Bioinformatics ; 20(1): 494, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604427

RESUMO

BACKGROUND: Literature derived knowledge assemblies have been used as an effective way of representing biological phenomenon and understanding disease etiology in systems biology. These include canonical pathway databases such as KEGG, Reactome and WikiPathways and disease specific network inventories such as causal biological networks database, PD map and NeuroMMSig. The represented knowledge in these resources delineates qualitative information focusing mainly on the causal relationships between biological entities. Genes, the major constituents of knowledge representations, tend to express differentially in different conditions such as cell types, brain regions and disease stages. A classical approach of interpreting a knowledge assembly is to explore gene expression patterns of the individual genes. However, an approach that enables quantification of the overall impact of differentially expressed genes in the corresponding network is still lacking. RESULTS: Using the concept of heat diffusion, we have devised an algorithm that is able to calculate the magnitude of regulation of a biological network using expression datasets. We have demonstrated that molecular mechanisms specific to Alzheimer (AD) and Parkinson Disease (PD) regulate with different intensities across spatial and temporal resolutions. Our approach depicts that the mitochondrial dysfunction in PD is severe in cortex and advanced stages of PD patients. Similarly, we have shown that the intensity of aggregation of neurofibrillary tangles (NFTs) in AD increases as the disease progresses. This finding is in concordance with previous studies that explain the burden of NFTs in stages of AD. CONCLUSIONS: This study is one of the first attempts that enable quantification of mechanisms represented as biological networks. We have been able to quantify the magnitude of regulation of a biological network and illustrate that the magnitudes are different across spatial and temporal resolution.


Assuntos
Algoritmos , Encéfalo/metabolismo , Doenças Neurodegenerativas/metabolismo , Biologia de Sistemas/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Mapas de Interação de Proteínas , Transdução de Sinais
11.
Adv Exp Med Biol ; 1161: 133-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562628

RESUMO

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use. For example, the sphingolipid analog, fingolimod (also known as FTY720), was the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS), whose mechanisms of action (MOA) includes sequestration of pathogenic lymphocytes into secondary lymphoid organs, as well as astrocytic modulation, via down-regulation of the sphingosine 1-phosphate (S1P) receptor, S1P1, by in vivo-phosphorylated fingolimod. Though the cause of MS is still under debate, MS is considered to be an autoimmune demyelinating and neurodegenerative disease. This review summarizes the involvement of bioactive lipids (prostaglandins, leukotrienes, platelet-activating factors, lysophosphatidic acid, and S1P) in MS and the animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation, along with pharmacological inhibition, of lipid metabolic enzymes and lipid GPCRs revealed that each bioactive lipid has a unique role in regulating immune and neural functions, including helper T cell (TH1 and TH17) differentiation and proliferation, immune cell migration, astrocyte responses, endothelium function, and microglial phagocytosis. A systematic understanding of bioactive lipids in MS and EAE dredges up information about understudied lipid signaling pathways, which should be clarified in the near future to better understand MS pathology and to develop novel DMTs.


Assuntos
Encefalomielite Autoimune Experimental , Metabolismo dos Lipídeos , Lipídeos , Esclerose Múltipla , Doenças Neurodegenerativas , Animais , Modelos Animais de Doenças , Lipídeos/química , Esclerose Múltipla/fisiopatologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/fisiopatologia
12.
Elife ; 82019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31414985

RESUMO

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Complemento C3/metabolismo , Fatores Imunológicos/metabolismo , Ceratite Herpética/complicações , Doenças Neurodegenerativas/fisiopatologia , Células Receptoras Sensoriais/patologia , Animais , Modelos Animais de Doenças , Camundongos
13.
Neuron ; 103(3): 367-379, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394062

RESUMO

Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Circulação Cerebrovascular , Microvasos/patologia , Doenças Neurodegenerativas/etiologia , Acoplamento Neurovascular , Animais , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/fisiopatologia , Isquemia Encefálica/etiologia , Progressão da Doença , Endotélio Vascular/fisiopatologia , Humanos , Microcirculação , Micronutrientes/farmacocinética , Modelos Animais , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/prevenção & controle , Neuroimagem
14.
Neuron ; 103(4): 563-581, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437453

RESUMO

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.


Assuntos
Plasticidade Neuronal/fisiologia , Neurotransmissores/fisiologia , Potenciais de Ação , Animais , Astrócitos/fisiologia , Comportamento/fisiologia , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Mapeamento Encefálico , Humanos , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Modelos Neurológicos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/fisiologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Terminações Pré-Sinápticas/fisiologia , Receptores de Neurotransmissores/fisiologia , Transdução de Sinais/fisiologia , Especificidade da Espécie , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Fatores de Tempo
15.
Intern Med ; 58(13): 1851-1858, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257275

RESUMO

Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. Methods and Patients Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. Results The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/mortalidade , Predisposição Genética para Doença , Neurônios Motores/fisiologia , Debilidade Muscular/fisiopatologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/fisiopatologia , Grupo com Ancestrais do Continente Asiático , Evolução Fatal , Feminino , Genótipo , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Mutação , Doenças Neurodegenerativas/mortalidade , Fenótipo
16.
Artigo em Inglês | MEDLINE | ID: mdl-31192157

RESUMO

Despite major strides in personalized genomics, it remains poorly understood why neurodegenerative diseases occur in only a fraction of individuals with a genetic predisposition and conversely, why individuals with no genetic risk of a disorder develop one. Chronic diseases like Alzheimer's, Parkinson's, and Multiple sclerosis are speculated to result from a combination of genetic and environmental factors, a concept commonly referred to as the "multiple hit hypothesis." A number of bacterial infections have been linked to increased risk of neurodegeneration, and in some cases, clearance of bacterial pathogens has been correlated with amelioration of central nervous system (CNS) deficits. Additionally, mutations in several genes known to contribute to CNS disorders like Parkinson's Disease have repeatedly been implicated in susceptibility to intracellular bacterial infection. Recent data has begun to demonstrate roles for these genes (PARK2, PINK1, and LRRK2) in modulating innate immune outcomes, suggesting that immune dysregulation may play an even more important role in neurodegeneration than previously appreciated. This review will broadly explore the connections between bacterial infection, immune dysregulation, and CNS disorders. Understanding this interplay and how bacterial pathogenesis contributes to the "multiple-hit hypothesis" of neurodegeneration will be crucial to develop therapeutics to effectively treat both neurodegeneration and infection.


Assuntos
Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Imunidade Inata , Doenças Neurodegenerativas/fisiopatologia , Esclerose Múltipla/fisiopatologia , Doença de Parkinson/fisiopatologia
17.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234550

RESUMO

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.


Assuntos
Flavonoides/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Flavonoides/farmacologia , Humanos , Doença de Huntington/tratamento farmacológico , Inflamação , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico
18.
PLoS Biol ; 17(6): e3000346, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31246996

RESUMO

Some neurodegenerative diseases, like Parkinsons Disease (PD) and Spinocerebellar ataxia 3 (SCA3), are associated with distinct, altered gait and tremor movements that are reflective of the underlying disease etiology. Drosophila melanogaster models of neurodegeneration have illuminated our understanding of the molecular mechanisms of disease. However, it is unknown whether specific gait and tremor dysfunctions also occur in fly disease mutants. To answer this question, we developed a machine-learning image-analysis program, Feature Learning-based LImb segmentation and Tracking (FLLIT), that automatically tracks leg claw positions of freely moving flies recorded on high-speed video, producing a series of gait measurements. Notably, unlike other machine-learning methods, FLLIT generates its own training sets and does not require user-annotated images for learning. Using FLLIT, we carried out high-throughput and high-resolution analysis of gait and tremor features in Drosophila neurodegeneration mutants for the first time. We found that fly models of PD and SCA3 exhibited markedly different walking gait and tremor signatures, which recapitulated characteristics of the respective human diseases. Selective expression of mutant SCA3 in dopaminergic neurons led to a gait signature that more closely resembled those of PD flies. This suggests that the behavioral phenotype depends on the neurons affected rather than the specific nature of the mutation. Different mutations produced tremors in distinct leg pairs, indicating that different motor circuits were affected. Using this approach, fly models can be used to dissect the neurogenetic mechanisms that underlie movement disorders.


Assuntos
Análise da Marcha/métodos , Marcha/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/fisiologia , Extremidades , Processamento de Imagem Assistida por Computador/instrumentação , Doença de Machado-Joseph , Aprendizado de Máquina , Movimento/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson
19.
Gac Med Mex ; 155(3): 276-283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31219465

RESUMO

Neurodegenerative diseases are a group of heterogeneous diseases characterized by a gradual, progressive and selective decrease in nervous system functions. The etiology of these pathologies remains unknown; however, mitochondrial function has been proposed as a common factor that could be involved in the establishment of these diseases, owing to the high energy requirement neurons have in order to carry out their physiological functions. Mitochondria are extremely dynamic organelles that can change their morphology and function in response to different physiological stimuli and, for this reason, mitochondrial dynamics have started being studied as one of cell survival main regulators. This event comprises different processes, such as the generation of new mitochondria and their elimination when they are no longer functional, as well as mitochondrial fusion and fission processes and the traffic of these organelles within the cellular environment. All these processes are highly regulated, and their main purpose is optimal functionality of mitochondria and cellular homeostasis.


Assuntos
Mitocôndrias/patologia , Doenças Neurodegenerativas/fisiopatologia , Animais , Sobrevivência Celular/fisiologia , Homeostase , Humanos , Neurônios/metabolismo
20.
Int J Mol Sci ; 20(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212645

RESUMO

Currently the human population is aging faster. This leads to higher dependency rates and the transformation of health and social care to adapt to this aged population. Among the changes developed by this population is frailty. It is defined as a clinically detectable syndrome, related to the aging of multiple physiological systems, which prompts a situation of vulnerability. The etiology of frailty seems to be multifactorial and its pathophysiology is influenced by the interaction of numerous factors. Morley et al. propose four main mechanisms triggering the frailty: atherosclerosis, sarcopenia, cognitive deterioration and malnutrition, with their respective metabolic alterations. Malnutrition is associated with cognitive impairment or functional loss, but it is also known that an inadequate nutritional status predisposes to cognitive frailty. Additionally, nutritional factors that may influence vascular risk factors will potentially have an effect on dementia decline among patients with cognitive frailty. This review aims to describe the nutritional factors that have been researched so far which may lead to the development of frailty, and especially cognitive decline.


Assuntos
Disfunção Cognitiva/fisiopatologia , Idoso Fragilizado , Doenças Neurodegenerativas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/metabolismo , Feminino , Radicais Livres/metabolismo , Humanos , Masculino , Doenças Neurodegenerativas/metabolismo
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