scholarly journals The Role of Gut Microbiota in Aging and Aging Related Neurodegenerative Disorders: Insights from Drosophila Model

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 855
Author(s):  
Yan Kong ◽  
Liyuan Wang ◽  
Baichun Jiang
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Physiological Function ◽  
Time Dependent ◽  
Model Organisms ◽  
Gi Tract ◽  
Drosophila Model ◽  
Increased Susceptibility

Aging is characterized by a time dependent impairment of physiological function and increased susceptibility to death. It is the major risk factor for neurodegeneration. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main causes of dementia in the old population. Gut microbiota is a community of microorganisms colonized in the gastrointestinal (GI) tract. The alteration of gut microbiota has been proved to be associated with aging and aging related neurodegeneration. Drosophila is a powerful tool to study microbiota-mediated physiological and pathological functions. Here, we summarize the recent advances using Drosophila as model organisms to clarify the molecular mechanisms and develop a therapeutic method targeting microbiota in aging and aging-related neurodegenerative disorders.

scholarly journals Gut–Brain Axis and Neurodegeneration: State-of-the-Art of Meta-Omics Sciences for Microbiota Characterization

2020 ◽  
Vol 21 (11) ◽  
pp. 4045 ◽  
Author(s):  
Bruno Tilocca ◽  
Luisa Pieroni ◽  
Alessio Soggiu ◽  
Domenico Britti ◽  
Luigi Bonizzi ◽  
...  
Keyword(s):  
Nervous System ◽  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Integrated Approach ◽  
Microbial Genomes ◽  
Physiological Processes ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut–brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

scholarly journals Intestinal microbiota shapes gut physiology and regulates enteric neurons and glia

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fernando A. Vicentini ◽  
Catherine M. Keenan ◽  
Laurie E. Wallace ◽  
Crystal Woods ◽  
Jean-Baptiste Cavin ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
Neuronal Survival ◽  
Neuronal Loss ◽  
Structure And Function ◽  
Enteric Neurons ◽  
Intestinal Function ◽  
Gi Tract ◽  
Enteric Glia ◽  
And Function

Abstract Background The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. Results Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions Our results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies.

scholarly journals Tau Accumulation via Reduced BAG3-mediated Autophagy Is Required for GGGGCC Repeat Expansion-Induced Neurodegeneration

2019 ◽  
Author(s):  
Xue Wen ◽  
Ping An ◽  
Hexuan Li ◽  
Zijian Zhou ◽  
Yimin Sun ◽  
...  
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Motor Performance ◽  
Molecular Mechanisms ◽  
Repeat Expansion ◽  
Cag Repeats ◽  
Reduced Activity ◽  
Lateral Sclerosis

SUMMARYExpansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats (CAGr) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r. Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r-induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

scholarly journals Epigenetics of aging and disease: a brief overview

2019 ◽  
Author(s):  
Christina Pagiatakis ◽  
Elettra Musolino ◽  
Rosalba Gornati ◽  
Giovanni Bernardini ◽  
Roberto Papait
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Disorders ◽  
Potential Role ◽  
Molecular Level ◽  
Physiological Function ◽  
Regulate Gene Expression ◽  
Age Related ◽  
Genetic And Environmental Factors ◽  
Different Tissues

AbstractAging is an important risk factor for several human diseases such as cancer, cardiovascular disease and neurodegenerative disorders, resulting from a combination of genetic and environmental factors (e.g., diet, smoking, obesity and stress), which, at molecular level, cause changes in gene expression underlying the decline of physiological function. Epigenetics, which include mechanisms regulating gene expression independently of changes to DNA sequence, regulate gene expression by modulating the structure of chromatin or by regulating the binding of transcriptional machinery to DNA. Several studies showed that an impairment of epigenetic mechanisms promotes alteration of gene expression underlying several aging-related diseases. Alteration of these mechanisms is also linked with changes of gene expression that occurs during aging processes of different tissues. In this review, we will outline the potential role of epigenetics in the onset of two age-related pathologies, cancer and cardiovascular diseases.

Presynaptic dysfunction in Huntington's disease

2010 ◽  
Vol 38 (2) ◽  
pp. 488-492 ◽  
Author(s):  
José L. Rozas ◽  
Leonardo Gómez-Sánchez ◽  
Cristina Tomás-Zapico ◽  
José J. Lucas ◽  
Rafael Fernández-Chacón
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Motor Dysfunction ◽  
Drosophila Model ◽  
Glutamine Repeat ◽  
Mutant Forms ◽  
The Relationship

HD (Huntington's disease) is produced by the expression of mutant forms of the protein htt (huntingtin) containing a pathologically expanded poly-glutamine repeat. For unknown reasons, in HD patients and HD mouse models, neurons from the striatum and cerebral cortex degenerate and lead to motor dysfunction and dementia. Synaptic transmission in those neurons becomes progressively altered during the course of the disease. However, the relationship between synaptic dysfunction and neurodegeneration in HD is not yet clear. Are there early specific functional synaptic changes preceding symptoms and neurodegeneration? What is the role of those changes in neuronal damage? Recent experiments in a Drosophila model of HD have showed that abnormally increased neurotransmitter release might be a leading cause of neurodegeneration. In the present review, we summarize recently described synaptic alterations in HD animal models and discuss potential underlying molecular mechanisms.

scholarly journals Longevity: epigenetic and biomolecular aspects

2015 ◽  
Vol 6 (2) ◽  
pp. 105-117 ◽  
Author(s):  
Giusi Taormina ◽  
Mario G. Mirisola
Keyword(s):  
Simple Model ◽  
Molecular Mechanisms ◽  
Model Organisms ◽  
Intermittent Fasting ◽  
Epigenetic Mechanisms ◽  
Long Term Effects ◽  
Dietary Interventions ◽  
Aging Theories

AbstractMany aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity.

scholarly journals Mitophagy Regulates Neurodegenerative Diseases

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1876
Author(s):  
Xufeng Cen ◽  
Manke Zhang ◽  
Mengxin Zhou ◽  
Lingzhi Ye ◽  
Hongguang Xia
Keyword(s):  
Neurodegenerative Diseases ◽  
Signaling Pathways ◽  
Neurodegenerative Disorders ◽  
Essential Role ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Treatment Strategies ◽  
Metabolic Process ◽  
Recent Advances

Mitochondria play an essential role in supplying energy for the health and survival of neurons. Mitophagy is a metabolic process that removes dysfunctional or redundant mitochondria. This process preserves mitochondrial health. However, defective mitophagy triggers the accumulation of damaged mitochondria, causing major neurodegenerative disorders. This review introduces molecular mechanisms and signaling pathways behind mitophagy regulation. Furthermore, we focus on the recent advances in understanding the potential role of mitophagy in the pathogenesis of major neurodegenerative diseases (Parkinson’s, Alzheimer’s, Huntington’s, etc.) and aging. The findings will help identify the potential interventions of mitophagy regulation and treatment strategies of neurodegenerative diseases.

scholarly journals The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhipeng Zheng ◽  
Baohong Wang
Keyword(s):  
Liver Injury ◽  
Gut Microbiota ◽  
Liver Regeneration ◽  
Liver Diseases ◽  
Molecular Mechanisms ◽  
Short Chain Fatty Acids ◽  
Pathophysiological Process ◽  
Tryptophan Metabolites ◽  
Health And Disease

Diverse liver diseases undergo a similar pathophysiological process in which liver regeneration follows a liver injury. Given the important role of the gut-liver axis in health and diseases, the role of gut microbiota-derived signals in liver injury and regeneration has attracted much attention. It has been observed that the composition of gut microbiota dynamically changes in the process of liver regeneration after partial hepatectomy, and gut microbiota modulation by antibiotics or probiotics affects both liver injury and regeneration. Mechanically, through the portal vein, the liver is constantly exposed to gut microbial components and metabolites, which have immense effects on the immunity and metabolism of the host. Emerging data demonstrate that gut-derived lipopolysaccharide, gut microbiota-associated bile acids, and other bacterial metabolites, such as short-chain fatty acids and tryptophan metabolites, may play multifaceted roles in liver injury and regeneration. In this perspective, we provide an overview of the possible molecular mechanisms by which gut microbiota-derived signals modulate liver injury and regeneration, highlighting the potential roles of gut microbiota in the development of gut microbiota-based therapies to alleviate liver injury and promote liver regeneration.

scholarly journals Bcl-2homologueDebclenhancesα-synuclein-induced phenotypes inDrosophila

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2461 ◽  
Author(s):  
P. Githure M’Angale ◽  
Brian E. Staveley
Keyword(s):  
Neurodegenerative Disorders ◽  
Dopaminergic Neurons ◽  
Neuronal Degeneration ◽  
Altered Expression ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
The Common ◽  
Locomotor Ability

BackgroundParkinson disease (PD) is a debilitating movement disorder that afflicts 1–2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptoticBcl-2family members, in contrast, only twoBcl-2family genes have been identified inDrosophila melanogaster, the proapoptotic mitochondrial localizedDebcland the antiapoptoticBuffy. The expression of the human transgeneα-synuclein, a gene that is strongly associated with inherited forms of PD, in dopaminergic neurons (DA) of Drosophila, results in loss of neurons and locomotor dysfunction to model PD in flies. The altered expression ofDebclin the DA neurons and neuron-rich eye and along with the expression ofα-synucleinoffers an opportunity to highlight the role ofDebclin mitochondrial-dependent neuronal degeneration and death.ResultsThe directed overexpression ofDebclusing theDdc-Gal4transgene in the DA of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition ofDebclresulted in enhanced survival and improved climbing ability whereas the overexpression ofDebclin theα-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression ofDebclalong withBuffypartially counteracts theDebcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression ofDebclalong with the expression ofα-synucleinin the eye, enhanced the eye ablation that results from the overexpression ofDebcl. The co-expression ofBuffyalong withDebcloverexpression results in the rescue of the moderate developmental eye defects. The co-expression ofBuffyalong with inhibition ofDebclpartially restores the eye to a roughened eye phenotype.DiscussionThe overexpression ofDebclin DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression ofDebclalong withα-synucleinenhanced the PD-like phenotypes. The co-expression ofDebclalong withBuffysuppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role forDebclin neurodegenerative disorders.

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