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1.
Brain ; 145(12): 4349-4367, 2022 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-36074904

RESUMEN

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.


Asunto(s)
Mitofagia , Enfermedad de Parkinson , Humanos , Estudio de Asociación del Genoma Completo , Mitofagia/fisiología , Enfermedades Neurodegenerativas , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/genética , Proteínas tau/genética
2.
Br J Nurs ; 30(13): S4-S5, 2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34251859

RESUMEN

Suzy Cole, National Nurses Nutrition Group Committee Member (suzy.cole@nhs.net) and Natalie Welsh, Vice Chair National Nurses Nutrition Group, outline recent work from several nutrition professional groups.


Asunto(s)
Terapia Nutricional , Seguridad del Paciente , Seguridad , Humanos , Terapia Nutricional/efectos adversos , Terapia Nutricional/enfermería
4.
Br J Nurs ; 30(21): S3, 2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34839685
5.
J Cell Sci ; 126(Pt 2): 379-91, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23547086

RESUMEN

The formation and stability of epithelial adhesive systems, such as adherens junctions, desmosomes and tight junctions, rely on a number of cellular processes that ensure a dynamic interaction with the cortical cytoskeleton, and appropriate delivery and turnover of receptors at the surface. Unique signalling pathways must be coordinated to allow the coexistence of distinct adhesive systems at discrete sub-domains along junctions and the specific properties they confer to epithelial cells. Rho, Rac and Cdc42 are members of the Rho small GTPase family, and are well-known regulators of cell-cell adhesion. The spatio-temporal control of small GTPase activation drives specific intracellular processes to enable the hierarchical assembly, morphology and maturation of cell-cell contacts. Here, we discuss the small GTPase regulators that control the precise amplitude and duration of the levels of active Rho at cell-cell contacts, and the mechanisms that tailor the output of Rho signalling to a particular cellular event. Interestingly, the functional interaction is reciprocal; Rho regulators drive the maturation of cell-cell contacts, whereas junctions can also modulate the localisation and activity of Rho regulators to operate in diverse processes in the epithelial differentiation programme.


Asunto(s)
Adhesión Celular/fisiología , Proteínas de Unión al GTP rho/fisiología , Animales , Citoesqueleto/enzimología , Citoesqueleto/fisiología , Humanos , Transducción de Señal
7.
Br J Nurs ; 26(12): 670, 2017 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-28640715
8.
Haematologica ; 96(12): 1753-60, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21933862

RESUMEN

BACKGROUND: Controversy persists regarding the role of Notch signaling in myelopoiesis. We have used genetic approaches, employing two Notch zebrafish mutants deadly seven (DES) and beamter (BEA) with disrupted function of notch1a and deltaC, respectively, and Notch1a morphants to analyze the development of leukocyte populations in embryonic and mature fish. DESIGN AND METHODS: Myelomonocytes were quantified in early embryos by in situ hybridization using a myeloper-oxidase (mpx) probe. Morpholinos were used to knock down expression of Notch1a or DeltaC. Wound healing assays and/or flow cytometry were used to quantify myelomonocytes in 5-day post-fertilization (dpf) Notch mutants (BEA and DES), morphants or pu.1:GFP, mpx:GFP and fms:RFP transgenic embryos. Flow cytometry was performed on 2-3 month old mutant fish. RESULTS: The number of mpx(+) cells in embryos was reduced at 48 hpf (but not at 26 hpf) in DES compared to WT. At 5 dpf this was reflected by a reduction in the number of myelomonocytic cells found at the wound site in mutants and in Notch1a morphants. This was due to a reduced number of myelomonocytes developing rather than a deficit in the migratory ability since transient inhibition of Notch signaling using DAPT had no effect. The early deficit in myelopoiesis was maintained into later life, 2-3 month old BEA and DES fish having a decreased proportion of myelomonocytes in both the hematopoietic organ (kidney marrow) and the periphery (coelomic cavity). CONCLUSIONS: Our results indicate that defects in Notch signaling affect definitive hematopoiesis, altering myelopoiesis from the early stages of development into the adult.


Asunto(s)
Embrión no Mamífero/embriología , Proteínas de Homeodominio/metabolismo , Mielopoyesis/fisiología , Proteínas del Tejido Nervioso/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal/fisiología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Animales , Embrión no Mamífero/citología , Proteínas de Homeodominio/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Organismos Modificados Genéticamente/embriología , Organismos Modificados Genéticamente/genética , Receptor Notch1/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genética
9.
Cell Death Dis ; 9(3): 327, 2018 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-29491392

RESUMEN

Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related and incurable neurodegenerative diseases. Features of these diseases include pathological protein inclusions in affected neurons with TAR DNA-binding protein 43 (TDP-43), dipeptide repeat proteins derived from the C9ORF72 gene, and fused in sarcoma (FUS) representing major constituent proteins in these inclusions. Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases. A large number of seemingly disparate physiological functions are damaged in FTD/ALS. However, many of these damaged functions are regulated by signalling between the endoplasmic reticulum and mitochondria, and this has stimulated investigations into the role of endoplasmic reticulum-mitochondria signalling in FTD/ALS disease processes. Here, we review progress on this topic.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Demencia/metabolismo , Retículo Endoplásmico/metabolismo , Mitocondrias/metabolismo , Esclerosis Amiotrófica Lateral/genética , Animales , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Demencia/genética , Retículo Endoplásmico/genética , Humanos , Mitocondrias/genética , Transducción de Señal
10.
Cell Signal ; 27(9): 1905-13, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25957131

RESUMEN

The precise mechanisms via which Rac1 is activated by cadherin junctions are not fully known. In keratinocytes Rac1 activation by cadherin junctions requires EGFR signalling, but how EGFR does so is unclear. To address which activator could mediate E-cadherin signalling to Rac1, we investigated EGFR and two Rac1 GEFs, SOS1 and DOCK180. EGFR RNAi prevented junction-induced Rac1 activation and led to fragmented localization of E-cadherin at cadherin contacts. In contrast, depletion of another EGFR family member, ErbB3, did not interfere with either process. DOCK180 RNAi, but not SOS1, prevented E-cadherin-induced Rac1 activation. However, in a strong divergence from EGFR RNAi phenotype, DOCK180 depletion did not perturb actin recruitment or cadherin localisation at junctions. Rather, reduced DOCK180 levels impaired the resistance to mechanical stress of pre-formed cell aggregates. Thus, within the same cell type, EGFR and DOCK180 regulate Rac1 activation by newly-formed contacts, but control separate cellular events that cooperate to stabilise junctions.


Asunto(s)
Cadherinas/metabolismo , Queratinocitos/metabolismo , Transducción de Señal/fisiología , Proteína de Unión al GTP rac1/metabolismo , Cadherinas/genética , Adhesión Celular/fisiología , Células Cultivadas , Humanos , Queratinocitos/citología , Interferencia de ARN , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismo , Proteína de Unión al GTP rac1/genética
11.
Hum Gene Ther ; 20(6): 589-97, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19222350

RESUMEN

In vivo electroporation of plasmid DNA (DNA-EP) is an efficient and safe method for vaccines. It results in increased DNA uptake, enhances protein expression, and augments immune responses to the target antigen in a variety of species. To further improve the efficacy of DNA-EP, we evaluated small interfering RNA (siRNA) sequences targeting apoptotic genes as an adjuvant to cancer vaccine. Bak1 or Casp8 siRNA was coadministered with plasmid DNA encoding the extracellular and transmembrane domains of rat HER2 ECD.TM to BALB-neuT mice, which spontaneously develop HER2/neu-positive mammary tumors. The combination regimen significantly reduced spontaneous tumor progression in BALB-neuT mice, in an advanced disease setting, when compared with DNA-EP alone. The antitumor effect was associated with a noteworthy antibody isotype switch from IgG1 to IgG2a, when siRNA was coadministered with DNA-EP. CD8+ T cell responses increased significantly, as did the number of responders to vaccination. Coimmunization of siRNA and DNA-EP at the same physical location was essential for the enhanced therapeutic effect. Silencing of the targeted genes was confirmed by in vitro Western blots. siRNA sequences targeting apoptotic genes Bax and Fas did not improve tumor protection in this mouse model when compared with DNA-EP alone. These data demonstrate that some siRNA sequences can act in concert with DNA-EP to control HER2/neu-positive mammary carcinoma. These observations emphasize the potential of siRNA as adjuvant for therapeutic DNA vaccines.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Mamarias Experimentales/inmunología , ARN Interferente Pequeño/inmunología , Vacunación , Vacunas de ADN/inmunología , Vacunas de ADN/uso terapéutico , Animales , Formación de Anticuerpos/efectos de los fármacos , Caspasa 8/metabolismo , Modelos Animales de Enfermedad , Electroporación , Ensayo de Inmunoadsorción Enzimática , Femenino , Silenciador del Gen/efectos de los fármacos , Células HeLa , Humanos , Inmunidad Celular/efectos de los fármacos , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Plásmidos/genética , Ratas , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo
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