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1.
Alzheimers Dement ; 20(2): 819-836, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37791598

RESUMO

INTRODUCTION: We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS: We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions. RESULTS: We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Camundongos , Humanos , Animais , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Fosforilação , Apolipoproteínas E/metabolismo , Doença de Alzheimer/patologia , Fatores Imunológicos , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo
2.
Nat Med ; 29(5): 1243-1252, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37188781

RESUMO

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.


Assuntos
Doença de Alzheimer , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Heterozigoto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais
3.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894177

RESUMO

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Furina/metabolismo , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Resultado do Tratamento
4.
ACS Synth Biol ; 3(10): 708-16, 2014 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24933470

RESUMO

Transcription activator-like effectors (TALEs) are proteins secreted by Xanthomonas bacteria to aid the infection of plant species. TALEs assist infections by binding to specific DNA sequences and activating the expression of host genes. Recent results show that TALE proteins consist of a central repeat domain, which determines the DNA targeting specificity and can be rapidly synthesized de novo. Considering the highly modular nature of TALEs, their versatility, and the ease of constructing these proteins, this technology can have important implications for synthetic biology applications. Here, we review developments in the area with a particular focus on modifications for custom and controllable gene regulation.


Assuntos
Proteínas de Bactérias/genética , Biologia Sintética/métodos , Transativadores/genética , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Humanos , Plantas/microbiologia , Engenharia de Proteínas/métodos , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequências Repetitivas de Aminoácidos , Transativadores/química , Transativadores/metabolismo , Xanthomonas/genética , Xanthomonas/patogenicidade
5.
J Cell Biol ; 192(6): 1043-55, 2011 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-21422231

RESUMO

Lipins are phosphatidate phosphatases that generate diacylglycerol (DAG). In this study, we report that yeast lipin, Pah1p, controls the formation of cytosolic lipid droplets. Disruption of PAH1 resulted in a 63% decrease in droplet number, although total neutral lipid levels did not change. This was accompanied by an accumulation of neutral lipids in the endoplasmic reticulum (ER). The droplet biogenesis defect was not a result of alterations in neutral lipid ratios. No droplets were visible in the absence of both PAH1 and steryl acyltransferases when grown in glucose medium, even though the strain produces as much triacylglycerol as wild type. The requirement of PAH1 for normal droplet formation can be bypassed by a knockout of DGK1. Nem1p, the activator of Pah1p, localizes to a single punctum per cell on the ER that is usually next to a droplet, suggesting that it is a site of droplet assembly. Overall, this study provides strong evidence that DAG generated by Pah1p is important for droplet biogenesis.


Assuntos
Citosol/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Fosfatidato Fosfatase/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Diglicerídeos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Compostos Orgânicos/metabolismo , Fosfatidato Fosfatase/genética , Proteínas de Saccharomyces cerevisiae/genética
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