Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease

Neuron, Год журнала: 2019, Номер 103(4), С. 627 - 641.e7

Опубликована: Июнь 26, 2019

Язык: Английский

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Год журнала: 2021, Номер 121(4), С. 2545 - 2647

Опубликована: Фев. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Язык: Английский

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Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health

Gut Microbes, Год журнала: 2019, Номер 11(2), С. 135 - 157

Опубликована: Авг. 1, 2019

The human gastrointestinal (gut) microbiota comprises diverse and dynamic populations of bacteria, archaea, viruses, fungi, protozoa, coexisting in a mutualistic relationship with the host. When intestinal homeostasis is perturbed, function tract other organ systems, including brain, can be compromised. gut proposed to contribute blood-brain barrier disruption pathogenesis neurodegenerative diseases. While progress being made, better understanding interactions between microbes host cells, impact these have on signaling from brain now required. In this review, we summarise current evidence their metabolites integrity function, communication networks which they may modulate. We also discuss potential modulation strategies as therapeutic tools for promoting restoring health.

Язык: Английский

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Protein transmission in neurodegenerative disease

Nature Reviews Neurology, Год журнала: 2020, Номер 16(4), С. 199 - 212

Опубликована: Март 23, 2020

Язык: Английский

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PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

Molecular Neurodegeneration, Год журнала: 2020, Номер 15(1)

Опубликована: Март 13, 2020

Abstract That certain cell types in the central nervous system are more likely to undergo neurodegeneration Parkinson’s disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons substantia nigra pars compacta, have shared phenotype of large, distributed axonal networks, dense synaptic connections, and high basal levels neural activity. These features come at substantial bioenergetic cost, suggesting that these experience degree mitochondrial stress. In such context, mechanisms quality control play an especially important role maintaining neuronal survival. this review, we focus on understanding unique challenges faced by mitochondria summarize evidence dysfunction contributes pathogenesis death subpopulations. We then review mediated activation PINK1 Parkin, two genes carry mutations associated with autosomal recessive disease. conclude pinpointing critical gaps our knowledge Parkin function, propose connection between sporadic defects will lead us greater insights into question selective vulnerability.

Язык: Английский

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A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

eLife, Год журнала: 2020, Номер 9

Опубликована: Фев. 11, 2020

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated neurodegenerative diseases. While genetic environmental factors influence amyloid formation, molecular triggers and/or facilitators not well defined. Growing evidence suggests that non-identical proteins may accelerate reciprocal aggregation in prion-like fashion. humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli cell surface abundantly expressed by certain bacteria. In mice overexpressing human α-synuclein (αSyn), we reveal colonization curli-producing Escherichia coli promotes αSyn pathology brain. Curli expression is required for E. exacerbate αSyn-induced behavioral deficits, including intestinal motor impairments. Purified subunits biochemical assays, while oral treatment gut-restricted inhibitor prevents curli-mediated acceleration abnormalities. We propose exposure microbial amyloids gastrointestinal tract disease

Язык: Английский

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Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

Nature Neuroscience, Год журнала: 2020, Номер 23(3), С. 327 - 336

Опубликована: Фев. 17, 2020

Язык: Английский

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Frontiers in Pharmacology, Год журнала: 2020, Номер 11

Опубликована: Апрель 23, 2020

Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD characterized by the loss of dopaminergic neuronal cells substantia nigra pars compacta and abnormal accumulation aggregation α-Syn form Lewy bodies neurites. More precisely, associated with dysfunctionality degeneration neurons PD. Moreover, mutations SNCA gene, which encodes α-Syn, cause familial forms are basis sporadic risk. Given role pathology PD, animal models that reflect widespread progressive formation aggregates different areas brain constitute valuable tool. Indeed, important for understanding molecular mechanisms might contribute to development validation new therapies. In absence faithfully reproduce human recent years, numerous based on have been generated. this review, we summarize main features pre-formed fibrils (PFFs) model recombinant adeno-associated virus vector (rAAV) mediated overexpression models, providing detailed comparative analysis both models. Here, discuss how each has contributed our advantages weakness them.Here, show injection PFFs rAAV lead pattern rodents. First, trigger body-like inclusions regions directly interconnected site, suggesting there an inter-neuronal transmission contrast, rAAV-mediated limits within transduced neurons. Second, phosphorylated obtained predominantly nuclear punctate appearance becomes diffuse along fibers, whereas cytoplasmic reminiscent

Язык: Английский

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Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Journal of Parkinson s Disease, Год журнала: 2019, Номер 9(s2), С. S281 - S295

Опубликована: Сен. 3, 2019

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation misfolded alpha-synuclein and propagation these proteinacious aggregates through interconnected neural networks believed to be crucial pathogenetic factor. It has been hypothesized that the initial pathological originate in enteric or peripheral nervous system (PNS) invade central (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests not all PD patients can reconciled with this hypothesis. Importantly, small fraction do show pathology dorsal motor nucleus vagus. Here, it divided into PNS-first CNS-first subtype. The former tightly associated REM sleep behavior disorder (RBD) during prodromal phase characterized by marked autonomic damage before involvement dopaminergic system. In contrast, phenotype most often RBD-negative nigrostriatal dysfunction prior PNS. existence subtypes supported vivo imaging RBD-positive patient groups histological evidence- reviewed herein. present proposal provides fresh hypothesis-generating framework for future etiopathogenesis seems capable explaining number discrepant findings literature.

Язык: Английский

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Meta‐Analysis of Gut Dysbiosis in Parkinson's Disease

Movement Disorders, Год журнала: 2020, Номер 35(9), С. 1626 - 1635

Опубликована: Июнь 18, 2020

Abstract Background PD may begin with the intestinal accumulation of α‐synuclein fibrils, which can be causally associated gut dysbiosis. The variability microbiota across countries prevented us from identifying shared dysbiosis in PD. Objectives To identify countries. Methods We performed 16S ribosomal RNA gene sequencing analysis 223 patients and 137 controls, meta‐analyzed by combining our dataset four previously reported data sets United States, Finland, Russia, Germany. excluded uncommon taxa analyses. For pathway analysis, we developed Kyoto Encyclopedia Genes Genomes orthology set enrichment method. Results After adjusting for confounding factors (body mass index, constipation, sex, age, catechol‐O‐methyl transferase inhibitor), genera Akkermansia Catabacter , as well families Akkermansiaceae were increased, whereas Roseburia Faecalibacterium Lachnospiraceae ND3007 group decreased Catechol‐O‐methyl inhibitor intake markedly increased family Lactobacillaceae . Inspection these bacteria 12 datasets that not included meta‐analysis revealed genus frequently observed changes short‐chain fatty acid metabolisms dataset. Conclusions report mucin layer‐degrading is acid–producing are © 2020 International Parkinson Movement Disorder Society

Язык: Английский

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