Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 11 de 11
Filtrer
Plus de filtres










Base de données
Gamme d'année
1.
Neuron ; 112(8): 1249-1264.e8, 2024 Apr 17.
Article de Anglais | MEDLINE | ID: mdl-38366598

RÉSUMÉ

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by cytoplasmic deposition of the nuclear TAR-binding protein 43 (TDP-43). Although cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, the underlying mechanisms remain unknown. Here, we identified a non-canonical interaction between 14-3-3θ and TDP-43, which regulates nuclear-cytoplasmic shuttling. Neuronal 14-3-3θ levels were increased in sporadic ALS and FTD with TDP-43 pathology. Pathogenic TDP-43 showed increased interaction with 14-3-3θ, resulting in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, resembling pathological changes in disease. Harnessing this increased affinity of 14-3-3θ for pathogenic TDP-43, we devised a gene therapy vector targeting TDP-43 pathology, which mitigated functional deficits and neurodegeneration in different ALS/FTD mouse models expressing mutant or non-mutant TDP-43, including when already symptomatic at the time of treatment. Our study identified 14-3-3θ as a mediator of cytoplasmic TDP-43 localization with implications for ALS/FTD pathogenesis and therapy.


Sujet(s)
Sclérose latérale amyotrophique , Démence frontotemporale , Animaux , Souris , Sclérose latérale amyotrophique/métabolisme , Protéines de liaison à l'ADN/génétique , Protéines de liaison à l'ADN/métabolisme , Démence frontotemporale/métabolisme , Neurones/métabolisme
2.
Neuropathol Appl Neurobiol ; 49(2): e12902, 2023 04.
Article de Anglais | MEDLINE | ID: mdl-36951214

RÉSUMÉ

AIMS: Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of upper and lower motor neurons leading to muscle weakness and eventually death. Frontotemporal dementia (FTD) presents clinically with significant behavioural decline. Approximately 10% of cases have a known family history, and disease-linked mutations in multiple genes have been identified in FTD and ALS. More recently, ALS and FTD-linked variants have been identified in the CCNF gene, which accounts for an estimated 0.6% to over 3% of familial ALS cases. METHODS: In this study, we developed the first mouse models expressing either wild-type (WT) human CCNF or its mutant pathogenic variant S621G to recapitulate key clinical and neuropathological features of ALS and FTD linked to CCNF disease variants. We expressed human CCNF WT or CCNFS621G throughout the murine brain by intracranial delivery of adeno-associated virus (AAV) to achieve widespread delivery via somatic brain transgenesis. RESULTS: These mice developed behavioural abnormalities, similar to the clinical symptoms of FTD patients, as early as 3 months of age, including hyperactivity and disinhibition, which progressively deteriorated to include memory deficits by 8 months of age. Brains of mutant CCNF_S621G mice displayed an accumulation of ubiquitinated proteins with elevated levels of phosphorylated TDP-43 present in both CCNF_WT and mutant CCNF_S621G mice. We also investigated the effects of CCNF expression on interaction targets of CCNF and found elevated levels of insoluble splicing factor proline and glutamine-rich (SFPQ). Furthermore, cytoplasmic TDP-43 inclusions were found in both CCNF_WT and mutant CCNF_S621G mice, recapitulating the key hallmark of FTD/ALS pathology. CONCLUSIONS: In summary, CCNF expression in mice reproduces clinical presentations of ALS, including functional deficits and TDP-43 neuropathology with altered CCNF-mediated pathways contributing to the pathology observed.


Sujet(s)
Sclérose latérale amyotrophique , Démence frontotemporale , Humains , Animaux , Souris , Nourrisson , Sclérose latérale amyotrophique/anatomopathologie , Démence frontotemporale/anatomopathologie , Motoneurones/anatomopathologie , Mutation , Protéines de liaison à l'ADN/métabolisme , Cyclines/génétique , Cyclines/métabolisme
3.
Acta Neuropathol ; 144(4): 637-650, 2022 10.
Article de Anglais | MEDLINE | ID: mdl-35780436

RÉSUMÉ

In Alzheimer's disease (AD), where amyloid-ß (Aß) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aß- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology.


Sujet(s)
Maladie d'Alzheimer , Protéines lysosomales membranaires/métabolisme , Maladie d'Alzheimer/anatomopathologie , Peptides bêta-amyloïdes/physiologie , Animaux , Modèles animaux de maladie humaine , Interneurones/anatomopathologie , Souris , Souris transgéniques , Neurones/anatomopathologie , Protéines tau/génétique
4.
Ecol Evol ; 12(4): e8848, 2022 Apr.
Article de Anglais | MEDLINE | ID: mdl-35475175

RÉSUMÉ

Extreme weather events are predicted to increase as a result of climate change, yet amphibian responses to extreme disturbance events remain understudied, especially in the Neotropics. Recently, an unprecedented windstorm within a protected Costa Rican rainforest opened large light gaps in sites where we have studied behavioral responses of diurnal strawberry poison frogs (Oophaga pumilio) to ultraviolet radiation for nearly two decades. Previous studies demonstrate that O. pumilio selects and defends perches where ultraviolet radiation (UV-B) is relatively low, likely because of the lethal and sublethal effects of UV-B. In this natural experiment, we quantified disturbance to O. pumilio habitat, surveyed for the presence of O. pumilio in both high-disturbance and low-disturbance areas of the forest, and assessed UV-B levels and perch selection behavior in both disturbance levels. Fewer frogs were detected in high-disturbance habitat than in low-disturbance habitat. In general, frogs were found vocalizing at perches in both disturbance levels, and in both cases, in significantly lower UV-B levels relative to ambient adjacent surroundings. However, frogs at perches in high-disturbance areas were exposed to UV-B levels nearly 10 times greater than males at perches in low-disturbance areas. Thus, behavioral avoidance of UV-B may not reduce the risks associated with elevated exposure under these novel conditions, and similarly, if future climate and human-driven land-use change lead to sustained analogous environments.

5.
Int J Mol Sci ; 22(15)2021 Jul 21.
Article de Anglais | MEDLINE | ID: mdl-34360544

RÉSUMÉ

The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43's underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD.


Sujet(s)
Sclérose latérale amyotrophique/anatomopathologie , Protéines de liaison à l'ADN/génétique , Démence frontotemporale/anatomopathologie , Inflammation/complications , Mutation , Sclérose latérale amyotrophique/étiologie , Sclérose latérale amyotrophique/métabolisme , Animaux , Démence frontotemporale/étiologie , Démence frontotemporale/métabolisme , Humains , Inflammation/classification
6.
J Gen Virol ; 102(5)2021 05.
Article de Anglais | MEDLINE | ID: mdl-33956593

RÉSUMÉ

Host cell lipids play a pivotal role in the pathogenesis of respiratory virus infection. However, a direct comparison of the lipidomic profile of influenza virus and rhinovirus infections is lacking. In this study, we first compared the lipid profile of influenza virus and rhinovirus infection in a bronchial epithelial cell line. Most lipid features were downregulated for both influenza virus and rhinovirus, especially for the sphingomyelin features. Pathway analysis showed that sphingolipid metabolism was the most perturbed pathway. Functional study showed that bacterial sphingomyelinase suppressed influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, but promoted rhinovirus replication. These findings suggest that sphingomyelin pathway can be a potential target for antiviral therapy, but should be carefully evaluated as it has opposite effects on different respiratory viruses. Furthermore, the differential effect of sphingomyelinase on rhinovirus and influenza virus may explain the interference between rhinovirus and influenza virus infection.


Sujet(s)
Orthomyxoviridae/effets des médicaments et des substances chimiques , Rhinovirus/effets des médicaments et des substances chimiques , SARS-CoV-2/effets des médicaments et des substances chimiques , Sphingomyéline/pharmacologie , Animaux , Maladies des bronches/virologie , Lignée cellulaire , Chiens , Cellules épithéliales/virologie , Humains , Grippe humaine , Lipidomique , Cellules rénales canines Madin-Darby , Infections à Orthomyxoviridae/traitement médicamenteux , Sphingomyeline phosphodiesterase , Réplication virale/effets des médicaments et des substances chimiques , Traitements médicamenteux de la COVID-19
7.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Article de Anglais | MEDLINE | ID: mdl-33737393

RÉSUMÉ

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer's disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-ß (oAß) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAß challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aß precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aß toxicity.


Sujet(s)
Peptides bêta-amyloïdes/métabolisme , Cycle cellulaire/physiologie , Neurones/physiologie , Maladie d'Alzheimer/étiologie , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Peptides bêta-amyloïdes/pharmacologie , Peptides bêta-amyloïdes/toxicité , Précurseur de la protéine bêta-amyloïde/génétique , Précurseur de la protéine bêta-amyloïde/métabolisme , Animaux , Marqueurs biologiques , Survie cellulaire/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Prédisposition aux maladies , Humains , Souris , Souris transgéniques
8.
Am J Pathol ; 190(8): 1713-1722, 2020 08.
Article de Anglais | MEDLINE | ID: mdl-32371051

RÉSUMÉ

Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43A315T in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43A315T by oral doxycycline treatment of iTDP-43A315T mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43A315T expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43A315T mice. Surprisingly, in contrast to the constitutive iTDP-43A315T mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43A315T expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43A315T expression in mature mice.


Sujet(s)
Encéphale/métabolisme , Protéines de liaison à l'ADN/génétique , Gliose/anatomopathologie , Troubles moteurs/génétique , Amyotrophie/génétique , Dégénérescence nerveuse/génétique , Animaux , Encéphale/anatomopathologie , Protéines de liaison à l'ADN/métabolisme , Souris , Souris transgéniques , Troubles moteurs/métabolisme , Troubles moteurs/anatomopathologie , Amyotrophie/métabolisme , Amyotrophie/anatomopathologie , Dégénérescence nerveuse/métabolisme , Dégénérescence nerveuse/anatomopathologie
9.
Int J Mol Sci ; 20(23)2019 Nov 26.
Article de Anglais | MEDLINE | ID: mdl-31779252

RÉSUMÉ

Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the most common causes of hand, foot, and mouth disease. Severe EV-A71 and CV-A16 infections may be associated with life-threatening complications. However, the pathogenic mechanisms underlying these severe clinical and pathological features remain incompletely understood. Lipids are known to play critical roles in multiple stages of the virus replication cycle. The specific lipid profile induced upon virus infection is required for optimal virus replication. The perturbations in the host cell lipidomic profiles upon enterovirus infection have not been fully characterized. To this end, we performed ultra-high performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (UPLC-ESI-Q-TOF-MS)-based lipidomics to characterize the change in host lipidome upon EV-A71 and CV-A16 infections. Our results revealed that 47 lipids within 11 lipid classes were significantly perturbed after EV-A71 and CV-A16 infection. Four polyunsaturated fatty acids (PUFAs), namely, arachidonic acid (AA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), were consistently upregulated upon EV-A71 and CV-A16 infection. Importantly, exogenously supplying three of these four PUFAs, including AA, DHA, and EPA, in cell cultures significantly reduced EV-A71 and CV-A16 replication. Taken together, our results suggested that enteroviruses might specifically modulate the host lipid pathways for optimal virus replication. Excessive exogenous addition of lipids that disrupted this delicate homeostatic state could prevent efficient viral replication. Precise manipulation of the host lipid profile might be a potential host-targeting antiviral strategy for enterovirus infection.


Sujet(s)
Entérovirus humain A/pathogénicité , Infections à entérovirus/métabolisme , Lipidomique/méthodes , Lignée cellulaire , Chromatographie en phase liquide à haute performance , Entérovirus humain A/classification , Infections à entérovirus/virologie , Homéostasie , Humains , Analyse en composantes principales , Spectrométrie de masse ESI , Réplication virale
10.
J Biol Chem ; 294(38): 14149-14162, 2019 09 20.
Article de Anglais | MEDLINE | ID: mdl-31366728

RÉSUMÉ

The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. We have previously recapitulated aspects of human FTD in mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology. The molecular mechanisms underlying the functional deficits of TAU58/2 mice remain mostly elusive. Here, we employed functional genomics (i.e. RNAseq) to determine differentially expressed genes in young and aged TAU58/2 mice to identify alterations in cellular processes that may contribute to neuropathy. We identified genes in cortical brain samples differentially regulated between young and old TAU58/2 mice relative to nontransgenic littermates and by comparative analysis with a dataset of CNS cell type-specific genes expressed in nontransgenic mice. Most differentially-regulated genes had known or putative roles in neurons and included presynaptic and excitatory genes. Specifically, we observed changes in presynaptic factors, glutamatergic signaling, and protein scaffolding. Moreover, in the aged mice, expression levels of several genes whose expression was annotated to occur in other brain cell types were altered. Immunoblotting and immunostaining of brain samples from the TAU58/2 mice confirmed altered expression and localization of identified and network-linked proteins. Our results have revealed genes dysregulated by progressive tau accumulation in an FTD mouse model.


Sujet(s)
Tauopathies/génétique , Tauopathies/métabolisme , Protéines tau/génétique , Maladie d'Alzheimer/métabolisme , Animaux , Encéphale/métabolisme , Système nerveux central/métabolisme , Modèles animaux de maladie humaine , Démence frontotemporale/génétique , Régulation de l'expression des gènes/génétique , Humains , Souris , Souris transgéniques , Neurones/métabolisme , Analyse de séquence d'ARN/méthodes , Tauopathies/physiopathologie , Protéines tau/métabolisme
11.
Am J Pathol ; 188(6): 1447-1456, 2018 06.
Article de Anglais | MEDLINE | ID: mdl-29577934

RÉSUMÉ

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.


Sujet(s)
Système nerveux central/anatomopathologie , Protéines de liaison à l'ADN/génétique , Modèles animaux de maladie humaine , Troubles moteurs/anatomopathologie , Amyotrophie/anatomopathologie , Maladies neurodégénératives/anatomopathologie , Vieillissement , Animaux , Système nerveux central/métabolisme , Protéines de liaison à l'ADN/métabolisme , Femelle , Humains , Mâle , Souris , Souris de lignée C57BL , Souris transgéniques , Troubles moteurs/génétique , Troubles moteurs/métabolisme , Amyotrophie/génétique , Amyotrophie/métabolisme , Mutation , Maladies neurodégénératives/génétique , Maladies neurodégénératives/métabolisme , Analyse spatio-temporelle
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE