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‣ Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

Cardoso, Susana; Santos, Renato; Correia, Sonia; Carvalho, Cristina; Zhu, Xiongwei; Lee, Hyoung-Gon; Casadesu, Gemma; Smith, Mark A.; Perry, George; Moreira, Paula I.
Fonte: Molecular Diversity Preservation International Publicador: Molecular Diversity Preservation International
Tipo: Revisão
Português
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Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore...

‣ Interplay between the Ubiquitin-Proteasome System and mechanisms of neurodegeneration in the context of Machado-Joseph disease (Tese corrigida)

Baptista, Márcio
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Tese de Doutorado
Português
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O Sistema Ubiquitina-Proteosoma (SUP) é um dos maiores sistemas de degradação regulada de proteínas. O sistema é essencial para a manutenção da homeostase e sinalização celulares. O tipo de ligação entre ubiquitinas e o seu comprimento vão definir o destino dos substratos ubiquitinados. A ubiquitinação de substratos pode ser revertida pela acção das enzimas desubiquitinadoras (DUBs). As DUBs podem actuar através da edição ou desmontagem das cadeias de poli-ubiquitina, são responsáveis pela clivagem dos precursores de ubiquitina, por evitar a degradação de substratos-alvo, pela edição das cadeias de ubiquitina à entrada do proteossoma e também pela manutenção das reservas celulares de ubiquitina livre. O papel do SUP nas doenças do sistema nervoso tem sido caracterizado ao longo dos últimos anos, e em particular nas doença de expansão de poliglutaminas, tendo começado por evidências de que componentes do SUP faziam parte dos agregados de proteínas desnaturadas. A ataxina 3 (ATXN3) é uma DUB presente em todos ou quase todos os tecidos do corpo humano e do murganho. As funções da ATXN3 vão desde a edição das proteínas poli-ubiquitinadas, ao sequestro de proteínas agregadas em agregossomas, à regulação da degradação proteica e resposta ao stress...

‣ Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy

PESTANA, Rafaela R. F.; KINJO, Erika R.; HERNANDES, Marina S.; BRITTO, Luiz R. G.
Fonte: ELSEVIER IRELAND LTD Publicador: ELSEVIER IRELAND LTD
Tipo: Artigo de Revista Científica
Português
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Reactive oxygen species (ROS) appear to be involved in several neurodegenerative disorders. We tested the hypothesis that oxidative stress could have a role in the hippocampal neurodegeneration observed in temporal lobe epilepsy induced by pilocarpine. We first determined the spatio-temporal pattern of ROS generation, by means of detection with dihydroethidium oxidation, in the CA1 and CA3 areas and the dentate gyrus of the dorsal hippocampus during status epilepticus induced by pilocarpine. Fluoro-Jade B assays were also performed to detect degenerating neurons. ROS generation was increased in CA1, CA3 and the dentate gyrus after pilocarpine-induced seizures, which was accompanied by marked cell death. Treatment of rats with a NADPH oxidase inhibitor (apocynin) for 7 days prior to induction of status epilepticus was effective in decreasing both ROS production (by an average of 20%) and neurodegeneration (by an average of 61%). These results suggest an involvement of ROS generated by NADPH oxidase in neuronal death in the pilocarpine model of epilepsy. (C) 2010 Elsevier Ireland Ltd. All rights reserved.; FAPESP; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); CNPq

‣ Lower isoflurane concentration affects spatial learning and neurodegeneration in adult mice compared with higher concentrations

Valentim, Ana; Giminiani, Pierpaolo; Ribeiro, Patrícia; Rodrigues, Paula; Olsson, Ana; Antunes, Luís
Fonte: American Society of Anesthesiologists Publicador: American Society of Anesthesiologists
Tipo: Artigo de Revista Científica
Português
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Background: Volatile anesthetics such as isoflurane are widely used in clinical and research contexts. Concerns have been raised that the effects of these drugs on the central nervous system may result in long-term impairment after surgery or general anesthesia. Hence, this study aimed to detect how different isoflurane concentrations influence spatial learning and cell death in adult mice. Methods: Fifty-two C57BL/6 mice were randomly divided in four groups. Mice in three groups were exposed to different concentrations of isoflurane (1, 1.5, and 2%) for 1 h; the control group was not exposed to anesthesia. Five mice per group were killed 3 h after anesthesia to perform histopathologic and immunohistochemical analyses (hematoxylin-eosin staining; caspase-3 activation). Eight mice per group were used for behavioral tests (open field, T-maze spontaneous alternation, and water maze) on subsequent days. Results: There were no differences between groups in the T-maze spontaneous alternation test or in the open field (no confounding effects of stress or locomotion). The group anesthetized with 1% isoflurane performed worse in the water maze task on day 1 (550.4 ±162.78 cm) compared with the control group (400.1 ± 112.88 cm), 1.5% isoflurane (351.9 ± 150.67 cm)...

‣ Different Concentrations of Ketamine did not Affect Cognition or Neurodegeneration in Adult Mice

Ribeiro, Patrícia; Valentim, Ana; Rodrigues, Paula; Antunes, Luís
Fonte: American Society of Anesthesiologists Publicador: American Society of Anesthesiologists
Tipo: Conferência ou Objeto de Conferência
Português
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Background: Ketamine is used in clinic how anesthetic and analgesic agent (1). However, little is known about the effects of the acute administration of this drug in brain of adult mice. The aim of this work was to study the effect of different concentrations of ketamine on cognition and its neurodegenerative effects. Methods: Forty-eight mice males, inbred C57BL/6, with 28 weeks old, were divided into 4 different groups (I- saline, II-25 mg/kg ketamine (KET), III-75mg/kg KET, IV-150mg/kg KET). Drugs were administered intraperitoneally (i.p.). Twenty-eight animals (n=7 per group) were behavioral tested with the Radial-maze task (during 12 consecutive days after anesthesia). Number of reference memory and working memory errors and time to finish the test were checked. The remaining 20 animals (n=5 per group) were sacrificed 3 hours after anesthesia by cervical dislocation followed by decapitation and their brains analyzed by hemotoxylin-eosin staining and caspase-3 activation to access neurodegeneration in the retrosplenial cortex, visual cortex, pyramidal cell layer from CA1 and CA3 areas of the hippocampus, and in the granular layer of the dentate gyrus. Death cells (H&E) and cells showing clear positive immunoreactions (caspase-3) were counted. Statistical analysis was performed using univariate ANOVA. Results: No significant differences were detected between groups on the behavior performance of the Radial-maze (fig.1). These observations were supported by similar results with histopatological studies (H&E and caspase 3 activation). Conclusion: This study showed no cognitive impairment or neurodegenerative differences induced by different concentrations of ketamine in the brain of adult mice.

‣ Temperature-sensitive paralytic mutants are enriched for those causing neurodegeneration in Drosophila.

Palladino, Michael J; Hadley, Tricia J; Ganetzky, Barry
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/2002 Português
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Age-dependent neurodegeneration is a pathological condition found in many metazoans. Despite the biological and medical significance of this condition, the cellular and molecular mechanisms underlying neurodegeneration are poorly understood. The availability of a large collection of mutants exhibiting neurodegeneration will provide a valuable resource to elucidate these mechanisms. We have developed an effective screen for isolating neurodegeneration mutants in Drosophila. This screen is based on the observation that neuronal dysfunction, which leads to observable behavioral phenotypes, is often associated with neurodegeneration. Thus, we used a secondary histological screen to examine a collection of mutants originally isolated on the basis of conditional paralytic phenotypes. Using this strategy, we have identified 15 mutations affecting at least nine loci that cause gross neurodegenerative pathology. Here, we present a genetic, behavioral, and anatomical analysis of vacuous (vacu), the first of these mutants to be characterized, and an overview of other mutants isolated in the screen. vacu is a recessive mutation located cytologically at 85D-E that causes locomotor defects in both larvae and adults as well as neuronal hyperactivity. In addition...

‣ Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia

Rimkus, Stacey A.; Katzenberger, Rebeccah J.; Trinh, Anthony T.; Dodson, Gerald E.; Tibbetts, Randal S.; Wassarman, David A.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em 01/05/2008 Português
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Mutations in ATM (Ataxia telangiectasia mutated) result in Ataxia telangiectasia (A-T), a disorder characterized by progressive neurodegeneration. Despite advances in understanding how ATM signals cell cycle arrest, DNA repair, and apoptosis in response to DNA damage, it remains unclear why loss of ATM causes degeneration of post-mitotic neurons and why the neurological phenotype of ATM-null individuals varies in severity. To address these issues, we generated a Drosophila model of A-T. RNAi knockdown of ATM in the eye caused progressive degeneration of adult neurons in the absence of exogenously induced DNA damage. Heterozygous mutations in select genes modified the neurodegeneration phenotype, suggesting that genetic background underlies variable neurodegeneration in A-T. The neuroprotective activity of ATM may be negatively regulated by deacetylation since mutations in a protein deacetylase gene, RPD3, suppressed neurodegeneration, and a human homolog of RPD3, histone deacetylase 2, bound ATM and abrogated ATM activation in cell culture. Moreover, knockdown of ATM in post-mitotic neurons caused cell cycle re-entry, and heterozygous mutations in the cell cycle activator gene String/CDC25 inhibited cell cycle re-entry and neurodegeneration. Thus...

‣ Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson’s disease

Kaur, Deepinder; Rajagopalan, Subramanian; Andersen, Julie K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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While ferritin elevation within dopaminergic (DA) neurons of the substantia nigra (SN) is protective against neurodegeneration elicited by two toxin models of Parkinson’s disease (PD), MPTP and paraquat, in young animals, its prolonged elevation results in a selective age-related neurodegeneration. A similar age-related neurodegeneration has been reported in iron regulatory protein 2-deficient (IRP2 −/−) mice coinciding with increased ferritin levels within degenerating neurons. This has been speculated to be due to subsequent reductions in the labile iron pool (LIP) needed for the synthesis of iron-sulfur-containing enzymes. In order to assess whether LIP reduction is responsible for age related-neurodegeneration in our ferritin transgenics, we examined LIP levels in ferritin-expressing transgenics with increasing age. While LIP levels were reduced within DA SN nerve terminals isolated from young ferritin transgenics compared to wildtype littermate controls, they were found to be increased in older transgenic animals at the age at which selective neurodegeneration is first noted. Furthermore, administration of the bioavailable iron chelator, clioquinol (CQ), to older mice was found to protect against both increased LIP and subsequent dopaminergic neurodegeneration. This suggests that age-related neurodegeneration in these mice is likely due to increased iron availability rather than its reduction. This may have important implications for PD and other related neurodegenerative conditions in which iron and ferritin have been implicated.

‣ Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration

Kruer, Michael C.; Hiken, Mark; Gregory, Allison; Malandrini, Alessandro; Clark, David; Hogarth, Penny; Grafe, Marjorie; Hayflick, Susan J.; Woltjer, Randall L.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Pantothenate kinase-associated neurodegeneration is a form of neurodegeneration with brain iron accumulation, characterized by a progressive movement disorder and prominent iron deposition in the globus pallidus. Formerly referred to as Hallervorden–Spatz syndrome, the disorder was renamed pantothenate kinase-associated neurodegeneration after discovery of the causative gene, PANK2. Although the pathological features of clinically characterized Hallervorden–Spatz syndrome have been described, the literature is confounded by the historical use of this term for nearly all conditions with prominent basal ganglia iron accumulation and by the fact that this term encompasses a genetically heterogeneous group of disorders, now referred to as ‘neurodegeneration with brain iron accumulation’. As a result, interpreting reports that precede molecular characterization of specific forms of neurodegeneration with brain iron accumulation is problematic. In the present studies, we describe neuropathological findings in six cases of molecularly confirmed pantothenate kinase-associated neurodegeneration. We identify prominent ubiquinated deposits in pantothenate kinase-associated neurodegeneration. We also characterize two distinct origins of spheroid bodies and delineate histological features of iron deposition. In so doing...

‣ In vivo Olfactory Model of APP-induced Neurodegeneration Reveals a Reversible Cell-autonomous Function

Cheng, Ning; Cai, Huaibin; Belluscio, Leonardo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 28/09/2011 Português
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Amyloid precursor protein (APP) has long been linked to the neurodegeneration of Alzheimer’s disease (AD), but the associated cell death has been difficult to capture in vivo, and the role of APP in effecting neuron loss is still unclear. Olfactory dysfunction is an early symptom of AD with amyloid pathology in the olfactory epithelium correlating well to the brain pathology of AD patients. As olfactory sensory neurons (OSNs) regenerate continuously with immature and mature OSNs co-existing in the same olfactory epithelium, we sought to utilize this unique system to study APP-induced neurodegeneration. Here we have developed an olfactory-based transgenic mouse model that overexpresses humanized-APP containing familial AD-mutations (hAPP) in either mature or immature OSNs, and found that despite the absence of extracellular plaques a striking number of apoptotic neurons were detected by 3 weeks of age. Importantly, apoptosis was restricted to the specific population overexpressing hAPP, either mature or immature OSNs, sparing those without hAPP. Interestingly, we observed that this widespread neurodegeneration could be rapidly rescued by reducing hAPP expression levels in immature neurons. Together, these data argue that overexpressing hAPP alone could induce cell-autonomous apoptosis in both mature and immature neurons...

‣ 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair

Sheng, Zijing; Oka, Sugako; Tsuchimoto, Daisuke; Abolhassani, Nona; Nomaru, Hiroko; Sakumi, Kunihiko; Yamada, Hidetaka; Nakabeppu, Yusaku
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Português
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8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG–paired adenine. Mutant mice lacking 8-oxo–2′-deoxyguanosine triphosphate–depleting (8-oxo–dGTP–depleting) MTH1 and/or 8-oxoG–excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH...

‣ The Innate Immune Response Transcription Factor Relish Is Necessary for Neurodegeneration in a Drosophila Model of Ataxia-Telangiectasia

Petersen, Andrew J.; Katzenberger, Rebeccah J.; Wassarman, David A.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /05/2013 Português
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Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants. Three lines of evidence indicate that ATM mutations cause neurodegeneration by activating the Nuclear Factor-κB (NF-κB) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in ATM mutants. Second, Relish mutations inhibited upregulation of IIR genes and neurodegeneration in ATM mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that Imd and Dif mutations did not affect neurodegeneration in ATM mutants. Imd encodes an activator of Relish in the response to gram-negative bacteria...

‣ Chemokines and Neurodegeneration in the Early Stage of Experimental Ischemic Stroke

Wolinski, Pawel; Glabinski, Andrzej
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
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Neurodegeneration is a hallmark of most of the central nervous system (CNS) disorders including stroke. Recently inflammation has been implicated in pathogenesis of neurodegeneration and neurodegenerative diseases. The aim of this study was analysis of expression of several inflammatory markers and its correlation with development of neurodegeneration during the early stage of experimental stroke. Ischemic stroke model was induced by stereotaxic intracerebral injection of vasoconstricting agent endothelin-1 (ET-1). It was observed that neurodegeneration appears very early in that model and correlates well with migration of inflammatory lymphocytes and macrophages to the brain. Although the expression of several studied chemotactic cytokines (chemokines) was significantly increased at the early phase of ET-1 induced stroke model, no clear correlation of this expression with neurodegeneration was observed. These data may indicate that chemokines do not induce neurodegeneration directly. Upregulated in the ischemic brain chemokines may be a potential target for future therapies reducing inflammatory cell migration to the brain in early stroke. Inhibition of inflammatory cell accumulation in the brain at the early stage of stroke may lead to amelioration of ischemic neurodegeneration.

‣ Exposure to Mitochondrial Genotoxins and Dopaminergic Neurodegeneration in Caenorhabditis elegans

González-Hunt, Claudia P.; Leung, Maxwell C. K.; Bodhicharla, Rakesh K.; McKeever, Madeline G.; Arrant, Andrew E.; Margillo, Kathleen M.; Ryde, Ian T.; Cyr, Derek D.; Kosmaczewski, Sara G.; Hammarlund, Marc; Meyer, Joel N.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 08/12/2014 Português
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Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration...

‣ Bases celulares y moleculares de la esclerosis lateral amiotrófica (ELA) : mecanismos neuronales de neurodegeneración y neuroprotección; Cellular and molecular basis of amyotrophic lateral sclerosis (ALS) : neuronal mechanisms of neurodegeneration and neuroprotection

Gonzalo Alonso, Isabel
Fonte: Universidade de Cantabria Publicador: Universidade de Cantabria
Tipo: Trabalho de Conclusão de Curso
Português
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La esclerosis lateral amiotrófica (ELA) se considera la patología neurodegenerativa de inicio en la edad adulta más devastadora. Se caracteriza por la progresiva degeneración y muerte de neuronas motoras superiores e inferiores. Entre los mecanismos implicados en su aparición se encuentra la alteración en la expresión de varios genes que explican los casos familiares de la enfermedad. La mayoría de los casos sin embargo son esporádicos. En ambos el hecho final común es la neurodegeneración y la pérdida neuronal. Recientemente se ha identificado que las formas esporádicas y familiares de ELA también comparten muchas de las vías moleculares patogénicas activadas (agregación proteica, estrés oxidativo, excitotoxicidad, alteración del procesamiento del RNA…) que conducen a este estado final, así como la identificación de la participación de células gliales en la enfermedad. Además se resalta la cierta selectividad del proceso por las motoneuronas y la gran reserva funcional que poseen, manifestándose la enfermedad en la mayoría de los casos en edades avanzadas sugiriendo medidas neuroprotectoras eficaces desarrolladas por las células durante años para compensar la neurodegeneración.; The amyotrophic lateral sclerosis (ALS) is regarded as the most devastating disease of adult-onset neurodegenerative disorders. It is characterised by progressive degeneration and death of both upper and lower motor neurons. Between the mechanisms involved in this pathology there are several gene alterations that explain the familial cases of the disease. However...

‣ Role of ERp57 in the regulation of gene expression and its involvement in neurodegeneration

AURELI, CRISTINA
Fonte: La Sapienza Universidade de Roma Publicador: La Sapienza Universidade de Roma
Tipo: Tese de Doutorado
Português
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Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by a progressive and selective loss of dopaminergic neurons in the Substantia nigra. Recent studies indicate that 5-S-cysteinyldopamine (CysDA), a catechol-thioether metabolite of dopamine (DA), is strongly neurotoxic and may contribute to the onset and progression of this disease (1). To better understand CysDA contribution to neurodegeneration, it has been evaluated the modulation of the expression, aggregation and cellular localization of proteins known to be involved in the oxidative stress response. In particular, we focused our study on alpha-Synuclein (a-Syn), a protein considered the PD “hallmark” and on ERp57, an endoplasmic reticulum thiol oxidoreductase, known to be implicated in neurodegenerative disease (2). To achieve these goals, both CD1 mice and SH-SY5Y neuroblastoma cells were treated with CysDA and the data were compared to those obtained by the use of 6-hydroxydopamine (6-OHDA), a well known parkinsonian mimetic. Intrastriatal injection of CysDA in CD1 mice caused a long-lasting depletion of DA, without affecting serotonergic or noradrenergic systems, providing in vivo evidence of CysDA specific neurotoxicity at dopaminergic system level. Both in CD1 mice and in SH-SY5Y cells...

‣ Alterações do metabolismo oxidativo mitocondrial e neurodegeneração por metilmalonato; Changes in mitochondrial oxidative metabolism and neurodegeneration by methymalonate

Daniela Rodrigues de Melo
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 17/02/2012 Português
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A acidemia metilmalônica é uma desordem metabólica hereditária envolvendo uma deficiência na atividade da enzima metilmalonil-CoA mutase, com resultante acúmulo de ácido metilmalônico (MMA) no organismo dos pacientes. Há evidências de comprometimento do metabolismo energético mitocondrial por MMA levando à neurodegeneração. Neste estudo avaliou-se o efeito in vitro de MMA no consumo de oxigênio por mitocôndrias isoladas de cérebro de rato na presença de diferentes substratos para a cadeia respiratória. MMA (1-10 mM) inibiu fortemente a respiração mantida por glutamato ou succinato. Nós confirmamos, por meio de experimentos sobre o transporte mitocondrial de succinato, que o efeito inibitório do MMA na respiração mantida por succinato deve-se à inibição do transportador mitocondrial de dicarboxilatos, impedindo a captação de succinato pela mitocôndria. Medidas do transporte mitocondrial de glutamato revelaram que o efeito do MMA na respiração mitocondrial mantida por glutamato não está relacionado à inibição da captação deste substrato pela mitocôndria. Enquanto o MMA mostrou um fraco efeito inibitório sobre a atividade das enzimas glutamato desidrogenase e aspartato transaminase, a atividade da 'alfa'-cetoglutarato desidrogenase foi significativamente inibida por MMA (Ki = 3...

‣ HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration

Gao, Hui-Ming; Zhou, Hui; Zhang, Feng; Wilson, Belinda C.; Kam, Wayneho; Hong, Jau-Shyong
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 19/01/2011 Português
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What drives the gradual degeneration of dopamine neurons in Parkinson's disease (PD), the second most common neurodegenerative disease, remains elusive. Here, we demonstrated, for the first time, that persistent neuroinflammation was indispensible for such neurodegenerative process. 1-methyl-4-phenylpyridinium, lipopolysaccharide (LPS), and rotenone, three toxins often used to create PD models, produced acute but nonprogressive neurotoxicity in neuron-enriched cultures. In the presence of microglia (brain immune cells), these toxins induced progressive dopaminergic neurodegeneration. More importantly, such neurodegeneration was prevented by removing activated microglia. Collectively, chronic neuroinflammation may be a driving force of progressive dopaminergic neurodegeneration. On the other hand, ongoing neurodegeneration sustained microglial activation. Microglial activation persisted only in the presence of neuronal damage in LPS-treated neuron-glia cultures, but not in LPS-treated mixed-glia cultures. Thus, activated microglia and damaged neurons formed a vicious cycle mediating chronic, progressive neurodegeneration. Mechanistic studies indicated that HMGB1 (high-mobility group box 1), released from inflamed microglia and/or degenerating neurons...

‣ Effects of mitochondrial dynamics genes, fzo-1 and drp-1, on dopaminergic neurodegeneration induced by environmental exposure in Caenorhabditis elegans, as a model of Parkinson’s disease

Hall, Samantha
Fonte: Universidade Duke Publicador: Universidade Duke
Publicado em 30/05/2015 Português
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Parkinson’s disease (PD) is caused by degeneration of the dopaminergic neurons; environmental toxicants are hypothesized to play a role in PD etiology. Environmental toxicants can cause mitochondrial dysfunction through mitochondrial DNA (mtDNA) damage and production of reactive oxygen species. Serial ultraviolet C (UVC) radiation causes an accumulation of mtDNA damage and 6-hydroxydopamine (6-OHDA) causes loss of dopaminergic neurons. Mitochondrial dynamics, or fusion and fission of the mitochondria, are important processes in mitigating mitochondrial dysfunction. The fzo-1 and drp-1 genes in Caenorhabditis elegans are orthologs for human Mfn1/2 and Drp1 and are involved in mitochondrial fusion and fission, respectively. I tested the hypothesis that deletion mutant strains for these two genes would show increased neurodegeneration after environmental damage, relative to the wild-type control strain, due to the lack of normal mitochondrial dynamics. Unexpectedly, both the fzo-1 and drp-1 were protected against 6-OHDA-induced neurodegeneration relative to wild-type. The fzo-1 knockout underwent complete larval arrest after UVC exposure, suggesting that mitochondrial fusion is necessary for recovery after mtDNA damage. The drp-1 mutant showed slightly more neurodegeneration than wild-type after UVC exposure at the 10 J/m2 dose...

‣ Apoptose e sistema complemento: mecanismos participantes da neurodegeneração na doença de Huntington; Apoptosis and complement system: participating mechanisms in Huntington´s disease neurodegeneration

Elias, Karina Maria; Diament, Mariela; Lima, Mário Luiz B. S. de; Valente, Tatiana; Silva, Kátia Cristina R. da; Gorescu, Rosa Alta
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion;
Publicado em 09/12/2001 Português
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A doença de Huntington (DH) é uma patologia neurodegenerativa de herança autossômica dominante, que,geralmente, tem início nas terceira e quarta décadas de vida. Atinge homens e mulheres na mesma proporção, sendo  maior sua prevalência em populações com ascendência da Europa Ocidental. As manifestações clínicas são progressivase abrangem distúrbios de movimentos (como coréia), demência e alterações da personalidade. A característicaanatomopatológica mais marcante é a atrofia cerebral, que predomina nas estruturas do corpo estriado (putâmen, globopálido e núcleo caudado). Estudos realizados em indivíduos portadores de DH levaram à descoberta e caracterizaçãoda proteína huntingtina (HDa), de papel fisiológico desconhecido. Devido a uma mutação, o gene IT-15, localizado no cromossomo 4, passa a codificar a HDa alterada, que possui expansão da poliglutamina em sua extremidade N-terminal. Por mecanismos ainda desconhecidos, esta HDa mutante é apontada como provável fator de indução da neurodegeneração. Têm-se atribuído como causa das manifestações clínicas a ocorrência de apoptose e a ativação do Sistema Complemento, sendo que ambas levam à morte neuronal. Este levantamento bibliográfico tem como objetivo estudar as recentes hipóteses sobre os mecanismos envolvidos na neurodegeneração da DH...