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1.
Am J Pathol ; 188(6): 1447-1456, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29577934

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease characterized by muscular atrophy because of loss of upper and lower motor neurons. Histopathologically, most patients with ALS have abnormal cytoplasmic accumulation and aggregation of the nuclear RNA-regulating protein TAR DNA-binding protein 43 (TDP-43). Pathogenic mutations in the TARDBP gene that encode TDP-43 have been identified in familial ALS. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice), presenting with early-onset motor deficits in adolescent animals. Here, we analyzed aged iTDP-43A315T mice, focusing on the spatiotemporal profile and progression of neurodegeneration in upper and lower motor neurons. Magnetic resonance imaging and histologic analysis revealed a differential loss of upper motor neurons in a hierarchical order as iTDP-43A315T mice aged. Furthermore, we report progressive gait problems, profound motor deficits, and muscle atrophy in aged iTDP-43A315T mice. Despite these deficits and TDP-43 pathologic disorders in lower motor neurons, stereological analysis did not show cell loss in spinal cords. Taken together, neuronal populations in aging iTDP-43A315T mice show differential susceptibility to the expression of human TDP-43A315T.


Assuntos
Sistema Nervoso Central/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Transtornos Motores/patologia , Atrofia Muscular/patologia , Doenças Neurodegenerativas/patologia , Envelhecimento , Animais , Sistema Nervoso Central/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos Motores/genética , Transtornos Motores/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Mutação , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Análise Espaço-Temporal
2.
Nat Commun ; 8(1): 473, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28883427

RESUMO

Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau-/-) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau-/- mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.Excitotoxicity contributes to neuronal injury following stroke. Here the authors show that tau promotes excitotoxicity by a post-synaptic mechanism, involving site-specific control of ERK activation, in a mouse model of stroke.


Assuntos
Lesões Encefálicas/genética , Modelos Animais de Doenças , Acidente Vascular Cerebral/genética , Proteínas tau/genética , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Transdução de Sinais/genética , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Sinaptossomos/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas tau/deficiência
3.
PLoS One ; 11(10): e0163236, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27736877

RESUMO

Several mouse lines with knockout of the tau-encoding MAPT gene have been reported in the past; they received recent attention due to reports that tau reduction prevented Aß-induced deficits in mouse models of Alzheimer's disease. However, the effects of long-term depletion of tau in vivo remained controversial. Here, we used the tau-deficient GFP knockin line Mapttm1(EGFP)kit on a pure C57Bl/6 background and subjected a large cohort of males and females to a range of motor, memory and behavior tests and imaging analysis, at the advanced age of over 16 months. Neither heterozygous nor homozygous Mapttm1(EGFP)kit mice presented with deficits or abnormalities compared to wild-type littermates. Differences to reports using other tau knockout models may be due to different genetic backgrounds, respective gene targeting strategies or other confounding factors, such as nutrition. To this end, we report no functional or morphological deficits upon tau reduction or depletion in aged mice.


Assuntos
Doença de Alzheimer/genética , Técnicas de Inativação de Genes , Proteínas tau/genética , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/genética , Locomoção , Masculino , Aprendizagem em Labirinto , Memória , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
4.
Acta Neuropathol ; 130(5): 661-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437864

RESUMO

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/fisiopatologia , Mutação , Recuperação de Função Fisiológica/fisiologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Doxiciclina , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Gliose/patologia , Gliose/fisiopatologia , Força da Mão/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Memória Espacial/fisiologia
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