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1.
Neuropathol Appl Neurobiol ; 47(3): 454-459, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33249605

RESUMO

Coronavirus disease 19 (COVID-19) is a rapidly evolving pandemic caused by the coronavirus Sars-CoV-2. Clinically manifest central nervous system symptoms have been described in COVID-19 patients and could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars-CoV-2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars-CoV-2-associated endotheliitis, which was associated by elevated levels of the Sars-CoV-2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension-related hemorrhage, critical illness-associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID-19 patients could be a consequence of Sars- CoV-2-induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.


Assuntos
COVID-19/complicações , Hemorragia Cerebral/patologia , Hemorragia Cerebral/virologia , Vasculite do Sistema Nervoso Central/patologia , Vasculite do Sistema Nervoso Central/virologia , Idoso , Idoso de 80 Anos ou mais , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , SARS-CoV-2
2.
Nature ; 501(7465): 102-6, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23903654

RESUMO

Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the α1 and α3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrP(C) mutant, PrP(Δ94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.


Assuntos
Anticorpos/imunologia , Anticorpos/toxicidade , Maleabilidade , Príons/química , Príons/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/toxicidade , Sítios de Ligação de Anticorpos , Calpaína/metabolismo , Cerebelo , Síndrome de Creutzfeldt-Jakob/metabolismo , Reagentes de Ligações Cruzadas , Mapeamento de Epitopos , Feminino , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/toxicidade , Técnicas In Vitro , Ligantes , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas PrPC/imunologia , Príons/genética , Espécies Reativas de Oxigênio/metabolismo , Deleção de Sequência/genética , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/toxicidade
3.
PLoS Pathog ; 12(1): e1005401, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26821311

RESUMO

Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.


Assuntos
Anticorpos Monoclonais/toxicidade , Imunoterapia/métodos , Proteínas PrPC/imunologia , Doenças Priônicas/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epitopos de Linfócito B/imunologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Priônicas/patologia
4.
PLoS Pathog ; 11(4): e1004808, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25875479

RESUMO

[This corrects the article DOI: 10.1371/journal.ppat.1004662.].

5.
PLoS Pathog ; 11(2): e1004662, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25710374

RESUMO

Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection.


Assuntos
Anticorpos , Proteínas PrPSc/imunologia , Doenças Priônicas/induzido quimicamente , Doenças Priônicas/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Animais , Anticorpos/imunologia , Anticorpos/toxicidade , Camundongos , Camundongos Transgênicos , Proteínas PrPSc/genética , Doenças Priônicas/genética , Doenças Priônicas/patologia , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais/genética , eIF-2 Quinase/genética , eIF-2 Quinase/imunologia
7.
Diagnostics (Basel) ; 14(13)2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-39001277

RESUMO

Dynamic perviousness is a novel imaging biomarker, with clot density measurements at multiple timepoints to allow longer contrast to thrombus interaction. We investigated the correlations between dynamic perviousness and clot composition in the setting of acute ischemic stroke. Thirty-nine patients with large vessel occlusion (LVO) undergoing mechanical thrombectomy (MT) were analyzed. Patients received a three-phase CT imaging pre-thrombectomy and histopathological analysis of retrieved clots. Clot densities for every phase and change in densities between phases were calculated, leading to four patterns of dynamic perviousness: no contrast uptake, early contrast uptake with and without washout and late uptake. Clots were categorized into three groups based on dominant histologic composition: red blood cell (RBC)-rich, fibrin/platelet-rich and mixed. Clot composition was correlated with dynamic perviousness using the Kruskal-Wallis test and Pearson's correlation analysis. The dynamic perviousness categories showed a significant difference between fibrin-rich clots when compared to RBC-rich plus mixed groups. The uptake without washout category had significantly fewer fibrin clots compared to the uptake with washout (p = 0.036), and nearly significantly fewer fibrin clots when compared to the no uptake category (p = 0.057). Contrast uptake with different patterns of contrast washout showed significant differences of the likelihood for fibrin-rich clots.

8.
EMBO Mol Med ; 16(9): 2024-2042, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39080493

RESUMO

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aß amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.


Assuntos
Amiloidose , Proteínas Adaptadoras de Sinalização CARD , Inflamassomos , Proteína Amiloide A Sérica , Animais , Proteína Amiloide A Sérica/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Amiloidose/metabolismo , Amiloidose/patologia , Humanos , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Agregados Proteicos , Camundongos Endogâmicos C57BL
9.
Front Oncol ; 13: 1254645, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37781183

RESUMO

Gliomas are the most common primary central nervous system (CNS) tumors and a major cause of cancer-related mortality in children (age <15 years), adolescents and young adults (AYA, ages 15-39 years), and adults (age >39 years). Molecular pathology has helped enhance the characterization of these tumors, revealing a heterogeneous and ever more complex group of malignancies. Recent molecular analyses have led to an increased appreciation of common genomic alterations prevalent across all ages. The 2021 World Health Organization (WHO) CNS tumor classification, 5th edition (WHO CNS5) brings forward a nomenclature distinguishing "pediatric-type" and "adult-type" gliomas. The spectrum of gliomas in AYA comprises both "pediatric-like" and "adult-like" tumor entities but remains ill-defined. With fragmentation of clinical management between pediatric and adult centers, AYAs face challenges related to gaps in medical care, lower rates of enrollment in clinical trials and additional psychosocial and economic challenges. This calls for a rethinking of diagnostic and therapeutic approaches, to improve access to appropriate testing and potentially beneficial treatments to patients of all ages.

10.
Brain Pathol ; 33(2): e13130, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329611

RESUMO

The cellular prion protein PrPC mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrPC (GDL) can also initiate neurotoxicity by inducing an intramolecular R208 -H140 hydrogen bond ("H-latch") between the α2-α3 and ß2-α2 loops of PrPC . Importantly, GDL that suppresses the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced 19 individual PrPC variants to PrPC -deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K27 or R27 ) within PrPC . Alanine substitution of K27 also prevented the toxicity of PrPC mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrPC . K27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.


Assuntos
Doenças Neurodegenerativas , Doenças Priônicas , Príons , Camundongos , Animais , Proteínas Priônicas/genética , Genética Reversa , Príons/genética , Anticorpos , Doenças Priônicas/genética
11.
Nat Struct Mol Biol ; 29(8): 831-840, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35948768

RESUMO

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond ('H-latch'), altering the flexibility of the α2-α3 and ß2-α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.


Assuntos
Proteínas PrPC , Príons , Animais , Anticorpos/metabolismo , Cerebelo/metabolismo , Ligantes , Camundongos , Proteínas PrPC/química , Proteínas PrPC/genética , Proteínas Priônicas/química , Proteínas Priônicas/genética , Proteínas Priônicas/metabolismo , Príons/metabolismo , Príons/toxicidade
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