RESUMO
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aß peptides. The shift in Aß length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aß peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aß. In contrast, E-Aßn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aß production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de Membrana/metabolismo , Peptídeo Hidrolases/metabolismo , Presenilina-1/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Endopeptidases , Estabilidade Enzimática , Feminino , Células HEK293 , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Modelos Moleculares , Mutação , Peptídeo Hidrolases/química , Peptídeo Hidrolases/genética , Presenilina-1/química , Presenilina-1/genéticaRESUMO
In this issue of Molecular Cell, Grieve et al. (2021) reveal Orai1/CRAC channels as atypical substrates of the RHBDL2 rhomboid and unveil the selective processing of stochastically activated CRAC channels by RHBLD2 as the "conformational surveillance" mechanism that prevents unwanted CRAC signaling in unstimulated cells.
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Transdução de Sinais , Prata , ProteóliseRESUMO
The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate1. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms2. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration3. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.
Assuntos
Indóis , Regeneração Nervosa , Propionatos , Cicatrização , Animais , Camundongos , Axônios/efeitos dos fármacos , Axônios/fisiologia , Quimiotaxia de Leucócito , Clostridium/metabolismo , Jejum , Gânglios Espinais/metabolismo , Microbioma Gastrointestinal , Indóis/sangue , Indóis/metabolismo , Indóis/farmacologia , Compressão Nervosa , Fatores de Crescimento Neural/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Neutrófilos/citologia , Neutrófilos/imunologia , Propionatos/sangue , Propionatos/metabolismo , Propionatos/farmacologia , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Análise de Sequência de RNA , Cicatrização/efeitos dos fármacosRESUMO
Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-ß (Aß) peptides and defines the proportion of short-to-long Aß peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aß peptide length. We found that polar interactions established by the APPC99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions. We show that increasing hydrophobicity, via mutation or ligand binding, at APPC99 -ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic γ-secretase and APP variants on Aß length. In addition, our study reveals that APPC99 -ECD facilitates the paradoxical production of longer Aßs caused by some γ-secretase inhibitors, which act as high-affinity competitors of the substrate. These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by γ-secretases and suggest it as a sweet spot for the potential design of APP-targeting compounds selectively promoting its processing by these enzymes.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/metabolismo , ProteóliseRESUMO
Alzheimer's disease (AD) pathogenesis has been linked to the accumulation of longer, aggregation-prone amyloid ß (Aß) peptides in the brain. Γ-secretases generate Aß peptides from the amyloid precursor protein (APP). Γ-secretase modulators (GSMs) promote the generation of shorter, less-amyloidogenic Aßs and have therapeutic potential. However, poorly defined drug-target interactions and mechanisms of action have hampered their therapeutic development. Here, we investigate the interactions between the imidazole-based GSM and its target γ-secretase-APP using experimental and in silico approaches. We map the GSM binding site to the enzyme-substrate interface, define a drug-binding mode that is consistent with functional and structural data, and provide molecular insights into the underlying mechanisms of action. In this respect, our analyses show that occupancy of a γ-secretase (sub)pocket, mediating binding of the modulator's imidazole moiety, is sufficient to trigger allosteric rearrangements in γ-secretase as well as stabilize enzyme-substrate interactions. Together, these findings may facilitate the rational design of new modulators of γ-secretase with improved pharmacological properties.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores e Moduladores de Secretases gama , Doença de Alzheimer/metabolismo , Imidazóis/uso terapêuticoRESUMO
The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aß peptides in Alzheimer's disease. The complex consists of four subunits, with Presenilin harboring the catalytic site. Here, we study the role of the smallest subunit, PSENEN or Presenilin enhancer 2, encoded by the gene Psenen, in vivo and in vitro. We find a profound Notch deficiency phenotype in Psenen-/- embryos confirming the essential role of PSENEN in the γ-secretase complex. We used Psenen-/- fibroblasts to explore the structure-function of PSENEN by the scanning cysteine accessibility method. Glycine 22 and proline 27, which border the membrane domains 1 and 2 of PSENEN, are involved in complex formation and stabilization of γ-secretase. The hairpin structured hydrophobic membrane domains 1 and 2 are exposed to a water-containing cavity in the complex, while transmembrane domain 3 is not water exposed. We finally demonstrate the essential role of PSENEN for the cleavage activity of the complex. PSENEN is more than a structural component of the γ-secretase complex and might contribute to the catalytic mechanism of the enzyme.
Assuntos
Secretases da Proteína Precursora do Amiloide , Animais , Feminino , Masculino , Camundongos , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Proteínas de Membrana/química , Camundongos Endogâmicos C57BL , Presenilina-1/genética , Estrutura Terciária de ProteínaRESUMO
Cerebral accumulation of amyloid-ß (Aß) initiates molecular and cellular cascades that lead to Alzheimer's disease (AD). However, amyloid deposition does not invariably lead to dementia. Amyloid-positive but cognitively unaffected (AP-CU) individuals present widespread amyloid pathology, suggesting that molecular signatures more complex than the total amyloid burden are required to better differentiate AD from AP-CU cases. Motivated by the essential role of Aß and the key lipid involvement in AD pathogenesis, we applied multimodal mass spectrometry imaging (MSI) and machine learning (ML) to investigate amyloid plaque heterogeneity, regarding Aß and lipid composition, in AP-CU versus AD brain samples at the single-plaque level. Instead of focusing on a population mean, our analytical approach allowed the investigation of large populations of plaques at the single-plaque level. We found that different (sub)populations of amyloid plaques, differing in Aß and lipid composition, coexist in the brain samples studied. The integration of MSI data with ML-based feature extraction further revealed that plaque-associated gangliosides GM2 and GM1, as well as Aß1-38, but not Aß1-42, are relevant differentiators between the investigated pathologies. The pinpointed differences may guide further fundamental research investigating the role of amyloid plaque heterogeneity in AD pathogenesis/progression and may provide molecular clues for further development of emerging immunotherapies to effectively target toxic amyloid assemblies in AD therapy. Our study exemplifies how an integrative analytical strategy facilitates the unraveling of complex biochemical phenomena, advancing our understanding of AD from an analytical perspective and offering potential avenues for the refinement of diagnostic tools.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Placa Amiloide , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico , Humanos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/análise , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/química , Encéfalo/metabolismo , Encéfalo/patologia , Lipídeos/análise , Lipídeos/química , Aprendizado de Máquina , IdosoRESUMO
Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing-remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4â +â T cells are pathogenic in RRMS, and defective T-cell function could be mediated in part by liver X receptors (LXRs)-nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4â +â T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T-cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4â +â T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4â +â T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
Assuntos
Linfócitos T CD4-Positivos , Metabolismo dos Lipídeos , Receptores X do Fígado , Esclerose Múltipla Recidivante-Remitente , Humanos , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores X do Fígado/metabolismo , Feminino , Adulto , Masculino , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Pessoa de Meia-Idade , Colesterol/metabolismo , Glicoesfingolipídeos/metabolismoRESUMO
BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.
Assuntos
Pessoas com Deficiência , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Biomarcadores , Proteínas de Neurofilamentos , Proteína Glial Fibrilar Ácida , Progressão da DoençaRESUMO
The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.
Assuntos
Colesterol/genética , Glicoesfingolipídeos/genética , Receptores X do Fígado/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Benzoatos/farmacologia , Benzilaminas/farmacologia , Membrana Celular , Colesterol/imunologia , Feminino , Glucosiltransferases/genética , Glicoesfingolipídeos/biossíntese , Glicoesfingolipídeos/imunologia , Humanos , Sinapses Imunológicas/efeitos dos fármacos , Sinapses Imunológicas/genética , Ligantes , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/imunologia , Receptores X do Fígado/agonistas , Receptores X do Fígado/antagonistas & inibidores , Receptores X do Fígado/genética , Masculino , Redes e Vias Metabólicas/imunologia , Pessoa de Meia-Idade , Oxisteróis/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto JovemRESUMO
Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.
Assuntos
Neoplasias Colorretais , Obesidade , Humanos , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Obesidade/complicações , Obesidade/metabolismo , Fatores de Risco , AnimaisRESUMO
γ-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD GSECs successively cut APP to generate amyloid-ß (Aß) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/Aßn interactions and thus enhance the production of longer Aßs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aßn during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APPC99 influences the stability of GSEC-Aßn assemblies and thereby modulates Aß length. The data suggest a potential link between single-nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aß length. Our findings may guide future rationale-based drug discovery efforts.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Glicoproteínas de Membrana/metabolismo , Domínios e Motivos de Interação entre Proteínas/fisiologia , Secretases da Proteína Precursora do Amiloide/química , Precursor de Proteína beta-Amiloide/química , Animais , Células Cultivadas , Ativação Enzimática , Espaço Extracelular , Células HEK293 , Humanos , Glicoproteínas de Membrana/química , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Quaternária de Proteína , Proteólise , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs). METHODS: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group-1, age ≤ 25, n = 62/46; Group-2, age = 26-49, n = 50/46; Group-3, age ≥ 50, n = 52/31) using multiple t-tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. RESULTS: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group-1), increased very-low-density lipoproteins (Group-2), and increased low-density lipoproteins (Group-3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein(Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type-1 and type-2 diabetes by disease-wide association. CONCLUSIONS: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.
RESUMO
Familial Alzheimer's disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid ß (Aß) peptides. Altered Aß metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aß42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aß42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aß profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aß profiles and AAO. In addition, our studies show that the Aß (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of 'unclear' PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aß profiles towards shorter Aß peptides.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Mutação/genética , Presenilina-1/genética , Presenilina-1/metabolismoRESUMO
The B-cell lymphoma 2 (Bcl-2) family of proteins is the main regulator of apoptosis. However, multiple emerging evidence has revealed that Bcl-2 family proteins are also involved in cellular senescence. On the one hand, the different expression of these proteins determines the entry into senescence. On the other hand, entry into senescence modulates the expression of these proteins, generally conferring resistance to apoptosis. With some exceptions, senescent cells are characterized by the upregulation of antiapoptotic proteins and downregulation of proapoptotic proteins. Under physiological conditions, freshly formed tetraploid cells die by apoptosis due to the tetraploidy checkpoint. However, suppression of Bcl-2 associated x protein (Bax), as well as overexpression of Bcl-2, favors the appearance and survival of tetraploid cells. Furthermore, it is noteworthy that our laboratory has shown that the joint absence of Bax and Bcl-2 antagonist/killer (Bak) favors the entry into senescence of tetraploid cells. Certain microtubule inhibitory chemotherapies, such as taxanes and vinca alkaloids, induce the generation of tetraploid cells. Moreover, the combined use of inhibitors of antiapoptotic proteins of the Bcl-2 family with microtubule inhibitors increases their efficacy. In this review, we aim to shed light on the involvement of the Bcl-2 family of proteins in the senescence program activated after tetraploidization and the possibility of using this knowledge to create a new therapeutic strategy targeting cancer cells.
Assuntos
Linfoma de Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Tetraploidia , Proteínas Reguladoras de Apoptose/metabolismo , Linfoma de Células B/metabolismo , Apoptose/fisiologia , Proteína bcl-X/metabolismoRESUMO
The rising prevalence of Alzheimer's disease (AD), together with the lack of effective treatments, portray it as one of the major health challenges of our times. Untangling AD implies advancing the knowledge of the biology that gets disrupted during the disease while deciphering the molecular and cellular mechanisms leading to AD-related neurodegeneration. In fact, a solid mechanistic understanding of the disease processes stands as an essential prerequisite for the development of safe and effective treatments. Genetics has provided invaluable clues to the genesis of the disease by revealing deterministic genes - Presenilins (PSENs) and the Amyloid Precursor Protein (APP) - that, when affected, lead in an autosomal dominant manner to early-onset, familial AD (FAD). PSEN is the catalytic subunit of the membrane-embedded γ-secretase complexes, which act as proteolytic switches regulating key cell signalling cascades. Importantly, these intramembrane proteases are responsible for the production of Amyloid ß (Aß) peptides from APP. The convergence of pathogenic mutations on one functional pathway, the amyloidogenic cleavage of APP, strongly supports the significance of this process in AD pathogenesis. Here, we review and discuss the state-of-the-art knowledge of the molecular mechanisms underlying FAD, their implications for the sporadic form of the disease and for the development of safe AD therapeutics.
Assuntos
Doença de Alzheimer/genética , Doenças Neurodegenerativas/genética , HumanosRESUMO
Manganese ferrite nanoparticles display interesting features in bioimaging and catalytic therapies. They have been recently used in theranostics as contrast agents in magnetic resonance imaging (MRI), and as catalase-mimicking nanozymes for hypoxia alleviation. These promising applications encourage the development of novel synthetic procedures to enhance the bioimaging and catalytic properties of these nanomaterials simultaneously. Herein, a cost-efficient synthetic microwave method is developed to manufacture ultrasmall manganese ferrite nanoparticles as advanced multimodal contrast agents in MRI and positron emission tomography (PET), and improved nanozymes. Such a synthetic method allows doping ferrites with Mn in a wide stoichiometric range (Mnx Fe3-x O4 , 0.1 ≤ x ≤ 2.4), affording a library of nanoparticles with different magnetic relaxivities and catalytic properties. These tuned magnetic properties give rise to either positive or dual-mode MRI contrast agents. On the other hand, higher levels of Mn doping enhance the catalytic efficiency of the resulting nanozymes. Finally, through their intracellular catalase-mimicking activity, these ultrasmall manganese ferrite nanoparticles induce an unprecedented tumor growth inhibition in a breast cancer murine model. All of these results show the robust characteristics of these nanoparticles for nanobiotechnological applications.
Assuntos
Meios de Contraste , Nanopartículas , Animais , Catalase , Compostos Férricos , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês , CamundongosRESUMO
There is an increased demand for food-grade grains grown sustainably. Hard red winter wheat has comparative advantages for organic farm rotations due to fall soil cover, weed competition, and grain yields. However, limitations of currently available cultivars such as poor disease resistance, winter hardiness, and baking quality, challenges its adoption and use. Our goal was to develop a participatory hard red winter wheat breeding program for the US Upper Midwest involving farmers, millers, and bakers. Specifically, our goals include (1) an evaluation of genotype-by-environment interaction (GEI) and genotypic stability for both agronomic and quality traits, and (2) the development of on-farm trials as well as baking and sensory evaluations of genotypes to include farmers, millers, and bakers' perspectives in the breeding process. Selection in early generations for diseases and protein content was followed by multi-environment evaluations for agronomic, disease, and quality traits in three locations during five years, on-farm evaluations, baking trials, and sensory evaluations. GEI was substantial for most traits, but no repeatable environmental conditions were significant contributors to GEI making selection for stability a critical trait. Breeding lines had similar performance in on-station and on-farm trials compared to commercial checks, but some breeding lines were more stable than the checks for agronomic, quality traits, and baking performance. These results suggest that stable lines can be developed using a participatory breeding approach under organic management. Crop improvement explicitly targeting sustainable agriculture practices for selection with farm to table participatory perspectives are critical to achieve long-term sustainable crop production. KEY MESSAGE: We describe a hard red winter wheat breeding program focused on developing genotypes adapted to organic systems in the US Upper Midwest for high-end artisan baking quality using participatory approaches.
Assuntos
Grão Comestível , Triticum , Grão Comestível/genética , Triticum/genética , Melhoramento VegetalRESUMO
In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-ß peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-ß (Aß)42:38, Aß42:40 and Aß38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-ß processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-ß between genotypes: higher Aß42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aß38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aß42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-ß profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aß42:38, Aß42:40 and Aß38:40 ratios and parental age at onset. In vivo differences in amyloid-ß processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.