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1.
J Neurosci ; 43(21): 3970-3984, 2023 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-37019623

RESUMEN

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedades por Prión , Priones , Masculino , Femenino , Ratones , Humanos , Animales , Priones/metabolismo , Proteínas Priónicas/metabolismo , Receptores AMPA/metabolismo , Neuronas/metabolismo , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Enfermedades Neurodegenerativas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo
2.
Neurobiol Dis ; 172: 105834, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35905927

RESUMEN

Synapse dysfunction and loss are central features of neurodegenerative diseases, caused in part by the accumulation of protein oligomers. Amyloid-ß, tau, prion, and α-synuclein oligomers bind to the cellular prion protein (PrPC), resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the early signaling events are unclear. Here we sought to determine the early transcript and protein alterations in the hippocampus during the pre-clinical stages of prion disease. We used a transcriptomic approach focused on the early-stage, prion-infected hippocampus of male wild-type mice, and identify immediate early genes, including the synaptic activity response gene, Arc/Arg3.1, as significantly upregulated. In a longitudinal study of male, prion-infected mice, Arc/Arg-3.1 protein was increased early (40% of the incubation period), and by mid-disease (pre-clinical), phosphorylated AMPA receptors (pGluA1-S845) were increased and metabotropic glutamate receptors (mGluR5 dimers) were markedly reduced in the hippocampus. Notably, sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger an early Arc response, followed by an increase in phosphorylated GluA1 and a reduction in mGluR5 receptors.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Priones , Péptidos beta-Amiloides/metabolismo , Animales , Síndrome de Creutzfeldt-Jakob/metabolismo , Hipocampo/metabolismo , Estudios Longitudinales , Masculino , Ratones , Priones/metabolismo
3.
Infect Immun ; 81(10): 3515-26, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23690397

RESUMEN

Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing L-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans.


Asunto(s)
Arginina/deficiencia , Bacteriemia/inmunología , Intestinos/citología , Malaria/complicaciones , Mastocitos/fisiología , Salmonelosis Animal/microbiología , Animales , Bacteriemia/microbiología , Citrulina , Femenino , Intestinos/inmunología , Intestinos/patología , Ratones , Permeabilidad , Plasmodium yoelii , Salmonelosis Animal/patología
4.
J Clin Invest ; 130(3): 1350-1362, 2020 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-31985492

RESUMEN

Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp180Q/196Q mice challenged with 2 subfibrillar, non-plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp180Q/196Q and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp187N) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.


Asunto(s)
Mutación Missense , Oligosacáridos/metabolismo , Enfermedades por Prión/metabolismo , Proteínas Priónicas/metabolismo , Agregación Patológica de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Sustitución de Aminoácidos , Animales , Ratones , Ratones Transgénicos , Oligosacáridos/genética , Enfermedades por Prión/genética , Enfermedades por Prión/patología , Proteínas Priónicas/genética , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología
5.
J Am Vet Med Assoc ; 235(6): 710-4, 2009 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-19751168

RESUMEN

CASE DESCRIPTION: A 6-year-old neutered male Boston Terrier was examined to determine the cause of sneezing, bilateral nasal discharge, nasal congestion, lethargy, and coughing of 2 months' duration. CLINICAL FINDINGS: An undifferentiated nasal carcinoma was diagnosed. During computed tomography (CT) evaluation of response to tomotherapy radiation treatment, a mandibular dentigerous cyst, associated with an unerupted left mandibular first premolar, was monitored for expansion. TREATMENT AND OUTCOME: The dog had a profound response to radiation treatment, and the nasal carcinoma totally resolved. It was determined on the basis of CT that the rate of expansion of the dentigerous cyst was placing the dog at risk for mandibular fracture and loss of vitality to the surrounding teeth. The unerupted left mandibular first premolar and associated dentigerous cyst were surgically removed and submitted for histologic evaluation. CLINICAL RELEVANCE: Images obtained during sequential CT evaluations performed after radiation treatment of nasal carcinoma should be examined for evidence of the primary neoplasm as well as to detect unrelated lesions of the orofacial region that can compromise the quality of life. Findings of CT evaluations can be used to determine when and how to initiate treatment for dentigerous cysts in regard to the patient's response to radiation treatment.


Asunto(s)
Carcinoma/veterinaria , Quistes Maxilomandibulares/veterinaria , Neoplasias Nasales/veterinaria , Tomografía Computarizada por Rayos X/veterinaria , Animales , Carcinoma/patología , Perros , Quistes Maxilomandibulares/diagnóstico por imagen , Masculino , Neoplasias Nasales/patología , Neoplasias Nasales/radioterapia
6.
Vet Clin North Am Small Anim Pract ; 37(6): 1151-65; vii-iii, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17950888

RESUMEN

Intensity-modulated radiation therapy (IMRT), especially image-guided IMRT as represented by helical tomotherapy, is a novel approach to therapy and is rapidly evolving. Both of these forms of therapy aim to allow targeted radiation delivery to the tumor volume while minimizing dose to the surrounding normal tissues. Adaptive radiation therapy and conformal avoidance are possible with intensity-modulated therapy and helical tomotherapy, which offer opportunities for improved local tumor control, decreased normal tissue toxicity, and improved survival and quality of life. Human and veterinary patients are likely to benefit from the continued development of this radiation delivery technique, and data over the next several years should be crucial in determining its true benefit.


Asunto(s)
Neoplasias/veterinaria , Radioterapia de Intensidad Modulada/veterinaria , Tomografía Computarizada Espiral/veterinaria , Animales , Neoplasias/radioterapia
7.
Vet Radiol Ultrasound ; 51(5): 561-70, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20973393

RESUMEN

Intensity-modulated radiation therapy (IMRT) allows optimization of radiation dose delivery to complex tumor volumes with rapid dose drop-off to surrounding normal tissues. A prospective study was performed to evaluate the concept of conformal avoidance using IMRT in canine sinonasal cancer. The potential of IMRT to improve clinical outcome with respect to acute and late ocular toxicity was evaluated. Thirty-one dogs with sinonasal cancer were treated definitively with IMRT using helical tomotherapy and/or dynamic multileaf collimator (DMLC) delivery. Ocular toxicity was evaluated prospectively and compared with a comparable group of historical controls treated with conventional two-dimensional radiotherapy (2D-RT) techniques. Treatment plans were devised for each dog using helical tomotherapy and DMLC that achieved the target dose to the planning treatment volume and limited critical normal tissues to the prescribed dose-volume constraints. Overall acute and late toxicities were limited and minor, detectable by an experienced observer. This was in contrast to the profound ocular morbidity observed in the historical control group treated with 2D-RT. Overall median survival for IMRT-treated and 2D-treated dogs was 420 and 411 days, respectively. Compared with conventional techniques, IMRT reduced dose delivered to eyes and resulted in bilateral ocular sparing in the dogs reported herein. These data provide proof-of-principle that conformal avoidance radiotherapy can be delivered through high conformity IMRT, resulting in decreased normal tissue toxicity as compared with historical controls treated with 2D-RT.


Asunto(s)
Enfermedades de los Perros/radioterapia , Neoplasias de los Senos Paranasales/veterinaria , Animales , Carcinoma/patología , Carcinoma/radioterapia , Carcinoma/veterinaria , Perros , Estadificación de Neoplasias , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/radioterapia , Selección de Paciente , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Conformacional/efectos adversos , Radioterapia Conformacional/métodos , Radioterapia Conformacional/veterinaria , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Radioterapia de Intensidad Modulada/veterinaria , Sarcoma/patología , Sarcoma/radioterapia , Sarcoma/veterinaria
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