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1.
Cell ; 183(3): 636-649.e18, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33031745

RESUMO

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Membrana/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Nucleotidiltransferases/metabolismo , Alarminas/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Citoplasma/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamação/metabolismo , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Degeneração Neural/patologia , Fosfotransferases (Aceptor do Grupo Álcool) , Subunidades Proteicas/metabolismo , Transdução de Sinais
2.
J Neuroinflammation ; 17(1): 222, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711529

RESUMO

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide; however, treatment development is hindered by the heterogenous nature of TBI presentation and pathophysiology. In particular, the degree of neuroinflammation after TBI varies between individuals and may be modified by other factors such as infection. Toxoplasma gondii, a parasite that infects approximately one-third of the world's population, has a tropism for brain tissue and can persist as a life-long infection. Importantly, there is notable overlap in the pathophysiology between TBI and T. gondii infection, including neuroinflammation. This paper will review current understandings of the clinical problems, pathophysiological mechanisms, and functional outcomes of TBI and T. gondii, before considering the potential synergy between the two conditions. In particular, the discussion will focus on neuroinflammatory processes such as microglial activation, inflammatory cytokines, and peripheral immune cell recruitment that occur during T. gondii infection and after TBI. We will present the notion that these overlapping pathologies in TBI individuals with a chronic T. gondii infection have the strong potential to exacerbate neuroinflammation and related brain damage, leading to amplified functional deficits. The impact of chronic T. gondii infection on TBI should therefore be investigated in both preclinical and clinical studies as the possible interplay could influence treatment strategies.


Assuntos
Lesões Encefálicas Traumáticas/microbiologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Toxoplasmose/complicações , Toxoplasmose/patologia , Animais , Encéfalo/microbiologia , Encéfalo/patologia , Gatos , Humanos , Inflamação , Toxoplasma
3.
Brain Behav Immun ; 80: 88-108, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30807837

RESUMO

Toxoplasma gondii (T. gondii) is a neurotropic parasite that is associated with various neuropsychiatric disorders. Rodents infected with T. gondii display a plethora of behavioural alterations, and Toxoplasma infection in humans has been strongly associated with disorders such as schizophrenia, in which impaired social behaviour is an important feature. Elucidating changes at the cellular level relevant to neuropsychiatric conditions can lead to effective therapies. Here, we compare changes in behaviour during an acute and chronic T. gondii infection in female mice. Further, we notice that during chronic phase of infection, mice display impaired sociability when exposed to a novel conspecific. Also, we show that T. gondii infected mice display impaired short-term social recognition memory. However, object recognition memory remains intact. Using c-Fos as a marker of neuronal activity, we show that infection leads to an impairment in neuronal activation in the medial prefrontal cortex, hippocampus as well as the amygdala when mice are exposed to a social environment and a change in functional connectivity between these regions. We found changes in synaptic proteins that play a role in the process of neuronal activation such as synaptophysin, PSD-95 and changes in downstream substrates of cell activity such as cyclic AMP, phospho-CREB and BDNF. Our results point towards an imbalance in neuronal activity that can lead to a wider range of neuropsychiatric problems upon T. gondii infection.


Assuntos
Cognição/fisiologia , Neurônios/metabolismo , Toxoplasmose/psicologia , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Comportamento Social , Sulfadiazina/farmacologia , Toxoplasma/metabolismo , Toxoplasma/patogenicidade , Toxoplasmose/metabolismo , Toxoplasmose Animal/psicologia
4.
Mol Cell Neurosci ; 86: 41-49, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29122705

RESUMO

Recent results indicate that STriatal-Enriched protein tyrosine Phosphatase (STEP) levels are regulated by brain-derived neurotrophic factor (BDNF), whose expression changes during postnatal development and aging. Here, we studied STEP ontogeny in mouse brain and changes in STEP with age with emphasis on the possible regulation by BDNF. We found that STEP expression increased during the first weeks of life, reaching adult levels by 2-3weeks of age in the striatum and cortex, and by postnatal day (P) 7 in the hippocampus. STEP protein levels were unaffected in BDNF+/- mice, but were significantly reduced in the striatum and cortex, but not in the hippocampus, of BDNF-/- mice at P7 and P14. In adult wild-type mice there were no changes in cortical and hippocampal STEP61 levels with age. Conversely, striatal STEP levels were reduced from 12months of age, correlating with higher ubiquitination and increased BDNF content and signaling. Lower STEP levels in older mice were paralleled by increased phosphorylation of its substrates. Since altered STEP levels are involved in cellular malfunctioning events, its reduction in the striatum with increasing age should encourage future studies of how this imbalance might participate in the aging process.


Assuntos
Envelhecimento/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Corpo Estriado/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/deficiência , Corpo Estriado/crescimento & desenvolvimento , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
5.
Neurobiol Dis ; 74: 41-57, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25449908

RESUMO

Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease.


Assuntos
Transtornos Cognitivos/fisiopatologia , Doença de Huntington/fisiopatologia , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D1/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Benzazepinas/farmacologia , Transtornos Cognitivos/etiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Doença de Huntington/complicações , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Pirimidinas/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , Triazóis/farmacologia
6.
Hippocampus ; 23(8): 684-95, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23576401

RESUMO

Huntington's disease (HD) causes motor disturbances, preceded by cognitive impairment, in patients and mouse models. We showed that increased hippocampal cAMP-dependent protein kinase (PKA) signaling disrupts recognition and spatial memories in R6 HD mouse models. However, unchanged levels of hippocampal phosphorylated (p) cAMP-responsive element-binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice. Here, we extend this finding by showing that nuclear pPKA catalytic subunit (Thr197) and pPKA substrate levels were unaltered in the hippocampus of R6/1 mice. Phosphodiesterases (PDEs) play an important role in the regulation of PKA activity. PDE10A, a cAMP/cGMP dual-substrate PDE, was reported to be restricted to the nuclear region in nonstriatal neurons. Using cell fractionation we confirmed that PDE10A was enriched in nuclear fractions, both in wild-type and R6/1 mice hippocampus, without differences in its levels or intracellular distribution between genotypes. We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice. Papaverine treatment improved spatial and object recognition memories in R6/1 mice, and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus. Papaverine likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase (cGK) substrates was not modified in either genotype. Moreover, hippocampal cAMP, but not cGMP, levels were increased after acute papaverine injection. Our results show that inhibition of PDE10 improves cognition in R6 mice, at least in part through increased GluA1 and CREB phosphorylation. Thus, PDE10 might be a good therapeutic target to improve cognitive impairment in HD.


Assuntos
Proteína de Ligação a CREB/metabolismo , Transtornos da Memória/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Reconhecimento Psicológico/fisiologia , Percepção Espacial/fisiologia , Análise de Variância , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Doença de Huntington/complicações , Doença de Huntington/genética , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Papaverina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Fosforilação/efeitos dos fármacos , Receptores de AMPA , Reconhecimento Psicológico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Percepção Espacial/efeitos dos fármacos , Fatores de Tempo , Repetições de Trinucleotídeos/genética
7.
Cell Rep ; 31(4): 107573, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32348768

RESUMO

Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner. Small RNA sequencing of sperm reveals significant transcriptional differences of infected animals compared to controls. Zygote microinjection of total small RNA from sperm of infected mice partially recapitulates the behavioral phenotype of naturally born offspring, suggesting an epigenetic mechanism of behavioral inheritance in the first generation. Our results demonstrate that sperm epigenetic factors can contribute to intergenerational inheritance of behavioral changes after pathogenic infection, which could have major public health implications.


Assuntos
Comportamento Animal/fisiologia , Epigenômica/métodos , Infecções/complicações , RNA/metabolismo , Espermatozoides/metabolismo , Toxoplasmose/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos
8.
Neurosci Biobehav Rev ; 96: 72-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476506

RESUMO

Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as it has far reaching public health implications for a parasite that is very common in human populations. Our current understanding centres on neuronal changes that are elicited directly by this intracellular parasite versus indirect changes that occur due to activation of the immune system within the CNS, or a combination of both. In this review, we explore the interactions between Toxoplasma and its host, the proposed mechanisms and consequences on neuronal function and mental health, and discuss Toxoplasma infection as a public health issue.


Assuntos
Toxoplasmose/fisiopatologia , Toxoplasmose/psicologia , Animais , Sistema Nervoso Central/parasitologia , Sistema Nervoso Central/fisiopatologia , Interações Hospedeiro-Parasita , Humanos , Transtornos Mentais/parasitologia , Transtornos Mentais/fisiopatologia , Toxoplasma , Toxoplasmose/parasitologia
9.
Mol Neurobiol ; 56(2): 1475-1487, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29948948

RESUMO

Striatal-enriched protein tyrosine phosphatase (STEP) modulates key signaling molecules involved in synaptic plasticity and neuronal function. It is postulated that STEP opposes the development of long-term potentiation (LTP) and that it exerts a restraint on long-term memory (LTM). Here, we examined whether STEP61 levels are regulated during hippocampal LTP and after training in hippocampal-dependent tasks. We found that after inducing LTP by high frequency stimulation or theta-burst stimulation STEP61 levels were significantly reduced, with a concomitant increase of STEP33 levels, a product of calpain cleavage. Importantly, inhibition of STEP with TC-2153 improved LTP in hippocampal slices. Moreover, we observed that after training in the passive avoidance and the T-maze spontaneous alternation task, hippocampal STEP61 levels were significantly reduced, but STEP33 levels were unchanged. Yet, hippocampal BDNF content and TrkB levels were increased in trained mice, and it is known that BDNF promotes STEP degradation through the proteasome. Accordingly, hippocampal pTrkBTyr816, pPLCγTyr783, and protein ubiquitination levels were increased in T-SAT trained mice. Remarkably, injection of the TrkB antagonist ANA-12 (2 mg/Kg, but not 0.5 mg/Kg) elicited LTM deficits and promoted STEP61 accumulation in the hippocampus. Also, STEP knockout mice outperformed wild-type animals in an age- and test-dependent manner. Summarizing, STEP61 undergoes proteolytic degradation in conditions leading to synaptic strengthening and memory formation, thus highlighting its role as a molecular constrain, which is removed to enable the activation of pathways important for plasticity processes.


Assuntos
Hipocampo/metabolismo , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Memória/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteólise , Ubiquitinação/fisiologia
10.
Prog Neurobiol ; 153: 18-45, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28377290

RESUMO

Dementia encapsulates a set of symptoms that include loss of mental abilities such as memory, problem solving or language, and reduces a person's ability to perform daily activities. Alzheimer's disease is the most common form of dementia, however dementia can also occur in other neurological disorders such as Huntington's disease (HD). Many studies have demonstrated that loss of neuronal cell function manifests pre-symptomatically and thus is a relevant therapeutic target to alleviate symptoms. Synaptopathy, the physiological dysfunction of synapses, is now being approached as the target for many neurological and psychiatric disorders, including HD. HD is an autosomal dominant and progressive degenerative disorder, with clinical manifestations that encompass movement, cognition, mood and behaviour. HD is one of the most common tandem repeat disorders and is caused by a trinucleotide (CAG) repeat expansion, encoding an extended polyglutamine tract in the huntingtin protein. Animal models as well as human studies have provided detailed, although not exhaustive, evidence of synaptic dysfunction in HD. In this review, we discuss the neuropathology of HD and how the changes in synaptic signalling in the diseased brain lead to its symptoms, which include dementia. Here, we review and discuss the mechanisms by which the 'molecular orchestras' and their 'synaptic symphonies' are disrupted in neurodegeneration and dementia, focusing on HD as a model disease. We also explore the therapeutic strategies currently in pre-clinical and clinical testing that are targeted towards improving synaptic function in HD.


Assuntos
Encéfalo/fisiopatologia , Demência/fisiopatologia , Doença de Huntington/fisiopatologia , Modelos Neurológicos , Neurotransmissores/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Animais , Demência/patologia , Medicina Baseada em Evidências , Humanos , Doença de Huntington/patologia , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Sinapses/patologia
11.
Mol Neurobiol ; 53(6): 4261-4273, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26223799

RESUMO

Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity. BDNF induced a reduction of STEP61 levels in primary cortical neurons, an effect that was prevented by inhibition of tyrosine kinases, phospholipase C gamma, or the ubiquitin-proteasome system (UPS). The levels of pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204), two STEP substrates, increased in BDNF-treated cultures, and blockade of the UPS prevented STEP61 degradation and reduced BDNF-induced GluN2B and ERK1/2 phosphorylation. Moreover, brief or sustained cell depolarization reduced STEP61 levels in cortical neurons by different mechanisms. BDNF also promoted UPS-mediated STEP61 degradation in cultured striatal and hippocampal neurons. In contrast, nerve growth factor and neurotrophin-3 had no effect on STEP61 levels. Our results thus indicate that STEP61 degradation is an important event in BDNF-mediated effects.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteólise/efeitos dos fármacos , Animais , Córtex Cerebral/citologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/citologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Neostriado/metabolismo , Fator de Crescimento Neural/farmacologia , Neurônios/metabolismo , Neurotrofina 3/farmacologia , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Ubiquitinação/efeitos dos fármacos
12.
Neuromolecular Med ; 15(2): 295-309, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23385980

RESUMO

Adenosine A2A receptor (A2AR) is a G-protein-coupled receptor highly expressed in basal ganglia. Its expression levels are severely reduced in Huntington's disease (HD), and several pharmacological therapies have shown its implication in this neurodegenerative disorder. The main goal of this study was to gain insight into the molecular mechanisms that regulate A2AR gene (ADORA2A) expression in HD. Based on previous data reported by our group, we measured the methylcytosine (5mC) and hydroxymethylcytosine (5hmC) content in the 5'UTR region of ADORA2A in the putamen of HD patients and in the striatum of R6/1 and R6/2 mice at late stages of the disease. In this genomic region, 5mC and 5hmC remained unchanged in both mice strains, although low striatal A2AR levels were associated with reduced 5mC levels in 30-week-old R6/1 mice and reduced 5hmC levels in 12-week-old R6/2 mice in exon m2. In order to analyze when this mechanism appears during the progression of the disease, a time course for A2AR protein levels was carried out in R6/1 mice striatum (8, 12, and 20 weeks of age). A2AR levels were reduced from 12 weeks of age onwards, and this downregulation was concomitant with reduced 5hmC levels in the 5'UTR region of ADORA2A. Interestingly, increased 5mC levels and reduced 5hmC were found in the 5'UTR region of ADORA2A in the putamen of HD patients with respect to age-matched controls. Therefore, an altered DNA methylation pattern in ADORA2A seems to play a role in the pathologically decreased A2AR expression levels found in HD.


Assuntos
Regiões 5' não Traduzidas/genética , 5-Metilcitosina/análise , Corpo Estriado/metabolismo , Citosina/análogos & derivados , Metilação de DNA , Doença de Huntington/genética , Putamen/metabolismo , Receptor A2A de Adenosina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Corpo Estriado/química , Citosina/análise , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Humanos , Proteína Huntingtina , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Putamen/química
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