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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360966

RESUMO

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas/métodos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Medicina de Precisão/métodos
2.
Free Radic Biol Med ; 172: 562-577, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34224817

RESUMO

Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease are characterized by progressive degeneration of synapses and neurons. Accumulation of misfolded/aggregated proteins represents a pathological hallmark of most neurodegenerative diseases, potentially contributing to synapse loss and neuronal damage. Emerging evidence suggests that misfolded proteins accumulate in the diseased brain at least in part as a consequence of excessively generated reactive oxygen species (ROS) and reactive nitrogen species (RNS). Mechanistically, not only disease-linked genetic mutations but also known risk factors for neurodegenerative diseases, such as aging and exposure to environmental toxins, can accelerate production of ROS/RNS, which contribute to protein misfolding - in many cases mimicking the effect of rare genetic mutations known to be linked to the disease. This review will focus on the role of RNS-dependent post-translational modifications, such as S-nitrosylation and tyrosine nitration, in protein misfolding and aggregation. Specifically, we will discuss molecular mechanisms whereby RNS disrupt the activity of the cellular protein quality control machinery, including molecular chaperones, autophagy/lysosomal pathways, and the ubiquitin-proteasome system (UPS). Because chronic accumulation of misfolded proteins can trigger mitochondrial dysfunction, synaptic damage, and neuronal demise, further characterization of RNS-mediated protein misfolding may establish these molecular events as therapeutic targets for intervention in neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas , Dobramento de Proteína , Humanos , Doenças Neurodegenerativas/genética , Óxido Nítrico , Oxirredução , Deficiências na Proteostase
3.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34115964

RESUMO

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Assuntos
Trifosfato de Adenosina/metabolismo , DNA Mitocondrial/biossíntese , Inflamassomos/efeitos dos fármacos , Metformina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/prevenção & controle , Animais , COVID-19/metabolismo , COVID-19/prevenção & controle , Citocinas/genética , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Metformina/uso terapêutico , Camundongos , Núcleosídeo-Fosfato Quinase/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/prevenção & controle , SARS-CoV-2/patogenicidade
5.
Antioxid Redox Signal ; 35(7): 531-550, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957758

RESUMO

Significance: Physiological concentrations of nitric oxide (NO•) and related reactive nitrogen species (RNS) mediate multiple signaling pathways in the nervous system. During inflammaging (chronic low-grade inflammation associated with aging) and in neurodegenerative diseases, excessive RNS contribute to synaptic and neuronal loss. "NO signaling" in both health and disease is largely mediated through protein S-nitrosylation (SNO), a redox-based posttranslational modification with "NO" (possibly in the form of nitrosonium cation [NO+]) reacting with cysteine thiol (or, more properly, thiolate anion [R-S-]). Recent Advances: Emerging evidence suggests that S-nitrosylation occurs predominantly via transnitros(yl)ation. Mechanistically, the reaction involves thiolate anion, as a nucleophile, performing a reversible nucleophilic attack on a nitroso nitrogen to form an SNO-protein adduct. Prior studies identified transnitrosylation reactions between glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-nuclear proteins, thioredoxin-caspase-3, and X-linked inhibitor of apoptosis (XIAP)-caspase-3. Recently, we discovered that enzymes previously thought to act in completely disparate biochemical pathways can transnitrosylate one another during inflammaging in an unexpected manner to mediate neurodegeneration. Accordingly, we reported a concerted tricomponent transnitrosylation network from Uch-L1-to-Cdk5-to-Drp1 that mediates synaptic damage in Alzheimer's disease. Critical Issues: Transnitrosylation represents a critical chemical mechanism for transduction of redox-mediated events to distinct subsets of proteins. Although thousands of thiol-containing proteins undergo S-nitrosylation, how transnitrosylation regulates a myriad of neuronal attributes is just now being uncovered. In this review, we highlight recent progress in the study of the chemical biology of transnitrosylation between proteins as a mechanism of disease. Future Directions: We discuss future areas of study of protein transnitrosylation that link our understanding of aging, inflammation, and neurodegenerative diseases. Antioxid. Redox Signal. 35, 531-550.

6.
J Neurovirol ; 27(3): 367-378, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33876414

RESUMO

In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.

7.
Proc Natl Acad Sci U S A ; 118(15)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33833060

RESUMO

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1ß (IL-1ß) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-ß peptide (Aß) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

8.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33692125

RESUMO

Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/metabolismo , S-Nitrosotióis/metabolismo , Esclerose Amiotrófica Lateral/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cisteína/metabolismo , Proteínas de Ligação a DNA/química , Demência Frontotemporal/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios Motores/metabolismo , Óxido Nítrico/metabolismo , Agregação Patológica de Proteínas , Processamento Pós-Transcricional do RNA , Espécies Reativas de Nitrogênio/metabolismo , S-Nitrosotióis/química , Estresse Fisiológico
9.
J Neurosci ; 41(10): 2264-2273, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33483428

RESUMO

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer's disease, and frontotemporal dementia. However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENT Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Células Cultivadas , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sinapses/metabolismo , Sinapses/patologia , alfa-Sinucleína/farmacologia
10.
Annu Rev Pharmacol Toxicol ; 61: 701-721, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-32997602

RESUMO

Excitatory/inhibitory (E/I) balance, defined as the balance between excitation and inhibition of synaptic activity in a neuronal network, accounts in part for the normal functioning of the brain, controlling, for example, normal spike rate. In many pathological conditions, this fine balance is perturbed, leading to excessive or diminished excitation relative to inhibition, termed E/I imbalance, reflected in network dysfunction. E/I imbalance has emerged as a contributor to neurological disorders that occur particularly at the extremes of life, including autism spectrum disorder and Alzheimer's disease, pointing to the vulnerability of neuronal networks at these critical life stages. Hence, it is important to develop approaches to rebalance neural networks. In this review, we describe emerging therapies that can normalize the E/I ratio or the underlying abnormality that contributes to the imbalance in electrical activity, thus improving neurological function in these maladies.

11.
Science ; 371(6526)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33273062

RESUMO

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.


Assuntos
Doença de Alzheimer/enzimologia , Quinase 5 Dependente de Ciclina/metabolismo , Dinaminas/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Sinapses/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Cisteína/genética , Cisteína/metabolismo , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Nitroarginina/farmacologia , Oxirredução , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Sinapses/patologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo
12.
Mol Psychiatry ; 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467645

RESUMO

Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.

13.
Antioxid Redox Signal ; 32(12): 817-833, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657228

RESUMO

Significance: Most brains affected by neurodegenerative diseases manifest mitochondrial dysfunction as well as elevated production of reactive oxygen species and reactive nitrogen species (RNS), contributing to synapse loss and neuronal injury. Recent Advances: Excessive production of RNS triggers nitric oxide (NO)-mediated post-translational modifications of proteins, such as S-nitrosylation of cysteine residues and nitration of tyrosine residues. Proteins thus affected impair mitochondrial metabolism, mitochondrial dynamics, and mitophagy in the nervous system. Critical Issues: Identification and better characterization of underlying molecular mechanisms for NO-mediated mitochondrial dysfunction will provide important insights into the pathogenesis of neurodegenerative disorders. In this review, we highlight recent discoveries concerning S-nitrosylation of the tricarboxylic acid cycle enzymes, mitochondrial fission GTPase dynamin-related protein 1, and mitophagy-related proteins Parkin and phosphatase and tensin homolog-induced putative kinase protein 1. We delineate signaling cascades affected by pathologically S-nitrosylated proteins that diminish mitochondrial function in neurodegenerative diseases. Future Directions: Further elucidation of the pathological events resulting from aberrant S-nitrosothiol or nitrotyrosine formation may lead to new therapeutic approaches to ameliorate neurodegenerative disorders.

14.
Elife ; 82019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782729

RESUMO

Human Alzheimer's disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.


Assuntos
Potenciais de Ação , Doença de Alzheimer/fisiopatologia , Cérebro/citologia , Excitabilidade Cortical , Fenômenos Eletrofisiológicos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/fisiologia , Precursor de Proteína beta-Amiloide/genética , Animais , Tamanho Celular , Células Cultivadas , Imunofluorescência , Humanos , Camundongos , Modelos Teóricos , Proteínas Mutantes/genética , Organoides , Presenilina-1/genética
15.
Neurobiol Dis ; 127: 390-397, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30928642

RESUMO

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipocampo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Animais , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
16.
Trends Mol Med ; 25(2): 72-74, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30611669

RESUMO

Direct cell reprogramming, the process by which a somatic cell is converted to another cell type, can potentially circumvent epigenetic changes and proliferative stages resulting from de-differentiation. Recently, Matsuda et al. (Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion; Neuronin in press) demonstrated that expression of transcription factor NeuroD1 can convert mouse microglia to neurons, both in vitro and in vivo.


Assuntos
Microglia , Neurônios , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Reprogramação Celular , Epigênese Genética , Humanos , Camundongos
17.
Curr Biol ; 28(17): R909-R914, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205056

RESUMO

Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species' neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.


Assuntos
Modelos Animais de Doenças , Desenvolvimento de Medicamentos/estatística & dados numéricos , Transtornos Mentais/tratamento farmacológico , Animais , Humanos , Camundongos , Neuropsiquiatria
18.
Nat Commun ; 9(1): 1070, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523838

RESUMO

The original version of the Supplementary Information associated with this Article inadvertently omitted Supplementary Table 1. The HTML has now been updated to include a corrected version of the Supplementary Information.

19.
Nat Commun ; 9(1): 817, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483518

RESUMO

Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.


Assuntos
Cardiolipinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Neurônios/metabolismo , Doença de Parkinson Secundária/genética , alfa-Sinucleína/genética , Animais , Anticorpos Monoclonais/farmacologia , Comunicação Celular , Diferenciação Celular , Linhagem Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Feminino , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/ultraestrutura , Mitofagia/efeitos dos fármacos , Mutação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Dobramento de Proteína/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , alfa-Sinucleína/metabolismo
20.
Cell Death Differ ; 25(3): 542-572, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29229998

RESUMO

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.


Assuntos
Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Biológicos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Animais , Humanos
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