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1.
Ann Clin Transl Neurol ; 9(10): 1551-1564, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36083004

RESUMO

OBJECTIVE: ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells. METHODS: We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis. RESULTS: Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment. INTERPRETATION: This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.


Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Drogas em Investigação , Fibroblastos/metabolismo , Humanos , RNA , Ácido Tauroquenodesoxicólico
2.
Hum Mol Genet ; 31(20): 3458-3477, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35652455

RESUMO

Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.


Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/metabolismo , Antioxidantes/metabolismo , Drogas em Investigação/metabolismo , Drogas em Investigação/uso terapêutico , Fibroblastos/metabolismo , Humanos , Transcriptoma/genética
3.
Endocrinol Diabetes Metab ; 4(1): e00191, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532622

RESUMO

Introduction: Sex differences in brain cortical function affect cognition, behaviour and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Oestrogen and oestrogen receptors (ERs), specifically ERß, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERß on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERß affects transcription. Methods: In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ERß knockout mice (n = 4/sex/genotype). We used unbiased clustering to analyse whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results: We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERßKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function 'cation channel activity'. Moreover, within each sex we found only a few DEGs in ERßKO vs WT mice (8 and 5 in males and females, respectively). Conclusions: Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ERß may be largely post-transcriptional.


Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Receptor beta de Estrogênio/fisiologia , Expressão Gênica/genética , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , Transcrição Gênica/genética
4.
Neurochem Res ; 44(10): 2336-2345, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30863968

RESUMO

Brain and heart ischemia are among the leading causes of death and disability in both men and women, but there are significant sex differences in the incidence and severity of these diseases. Ca2+ dysregulation in response to ischemia/reperfusion injury (I/RI) is a well-recognized pathogenic mechanism leading to the death of affected cells. Excess intracellular Ca2+ causes mitochondrial matrix Ca2+ overload that can result in mitochondrial permeability transition (MPT), which can have severe consequences for mitochondrial function and trigger cell death. Recent findings indicate that estrogens and their related receptors are involved in the regulation of MPT, suggesting that sex differences in I/RI could be linked to estrogen-dependent modulation of mitochondrial Ca2+. Here, we review the evidence supporting sex differences in I/RI and the role of estrogen and estrogen receptors in producing these differences, the involvement of mitochondrial Ca2+ overload in disease pathogenesis, and the estrogen-dependent modulation of MPT that may contribute to sex differences.


Assuntos
Mitocôndrias/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/fisiologia , Traumatismo por Reperfusão/metabolismo , Caracteres Sexuais , Animais , Cálcio/metabolismo , Humanos , Permeabilidade
5.
Neurobiol Learn Mem ; 154: 141-157, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29906573

RESUMO

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.


Assuntos
Doença de Alzheimer/fisiopatologia , Região CA1 Hipocampal/fisiologia , Canalopatias/fisiopatologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Plasticidade Neuronal , Células Piramidais/fisiologia , Potenciais de Ação , Envelhecimento , Animais , Região CA1 Hipocampal/ultraestrutura , Modelos Animais de Doenças , Retículo Endoplasmático/fisiologia , Feminino , Masculino , Camundongos Transgênicos , Células Piramidais/ultraestrutura
6.
Biochim Biophys Acta Bioenerg ; 1859(6): 423-433, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29550215

RESUMO

Recent evidence highlights a role for sex and hormonal status in regulating cellular responses to ischemic brain injury and neurodegeneration. A key pathological event in ischemic brain injury is the opening of a mitochondrial permeability transition pore (MPT) induced by excitotoxic calcium levels, which can trigger irreversible damage to mitochondria accompanied by the release of pro-apoptotic factors. However, sex differences in brain MPT modulation have not yet been explored. Here, we show that mitochondria isolated from female mouse forebrain have a lower calcium threshold for MPT than male mitochondria, and that this sex difference depends on the MPT regulator cyclophilin D (CypD). We also demonstrate that an estrogen receptor beta (ERß) antagonist inhibits MPT and knockout of ERß decreases the sensitivity of mitochondria to the CypD inhibitor, cyclosporine A. These results suggest a functional relationship between ERß and CypD in modulating brain MPT. Moreover, co-immunoprecipitation studies identify several ERß binding partners in mitochondria. Among these, we investigate the mitochondrial ATPase as a putative site of MPT regulation by ERß. We find that previously described interaction between the oligomycin sensitivity-conferring subunit of ATPase (OSCP) and CypD is decreased by ERß knockout, suggesting that ERß modulates MPT by regulating CypD interaction with OSCP. Functionally, in primary neurons and hippocampal slice cultures, modulation of ERß has protective effects against glutamate toxicity and oxygen glucose deprivation, respectively. Taken together, these results reveal a novel pathway of brain MPT regulation by ERß that could contribute to sex differences in ischemic brain injury and neurodegeneration.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte/genética , Ciclofilinas/genética , Receptor beta de Estrogênio/genética , Hipocampo/metabolismo , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Prosencéfalo/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Células COS , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Chlorocebus aethiops , Peptidil-Prolil Isomerase F , Ciclofilinas/antagonistas & inibidores , Ciclofilinas/deficiência , Ciclosporina/farmacologia , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/deficiência , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtomia , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , ATPases Mitocondriais Próton-Translocadoras , Piperidinas/farmacologia , Prosencéfalo/efeitos dos fármacos , Ligação Proteica , Pirazóis/farmacologia , Fatores Sexuais , Técnicas de Cultura de Tecidos
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