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1.
Cell Tissue Res ; 392(1): 215-234, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35084572

RESUMO

The prion protein (PrP) is a broadly expressed glycoprotein linked with a multitude of (suggested) biological and pathological implications. Some of these roles seem to be due to constitutively generated proteolytic fragments of the protein. Among them is a soluble PrP form, which is released from the surface of neurons and other cell types by action of the metalloprotease ADAM10 in a process termed 'shedding'. The latter aspect is the focus of this review, which aims to provide a comprehensive overview on (i) the relevance of proteolytic processing in regulating cellular PrP functions, (ii) currently described involvement of shed PrP in neurodegenerative diseases (including prion diseases and Alzheimer's disease), (iii) shed PrP's expected roles in intercellular communication in many more (patho)physiological conditions (such as stroke, cancer or immune responses), (iv) and the need for improved research tools in respective (future) studies. Deeper mechanistic insight into roles played by PrP shedding and its resulting fragment may pave the way for improved diagnostics and future therapeutic approaches in diseases of the brain and beyond.


Assuntos
Doenças Priônicas , Príons , Humanos , Proteínas Priônicas/metabolismo , Proteína ADAM10/metabolismo , Príons/metabolismo , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Encéfalo/metabolismo , Proteínas de Membrana/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo
2.
Acta Neuropathol ; 140(3): 317-339, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32577828

RESUMO

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer's disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We show that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem brains of rapidly progressive AD patients, sCJD patients and 3xTg mice brain at terminal stage of the disease. In contrast, the expression of SFPQ was elevated at early stage of the disease in the 3xTg mice, and in vitro after oxidative stress stimuli. Strikingly, in rpAD patients' brains SFPQ showed a significant dislocation from the nucleus and cytoplasmic colocalization with TIA-1. Furthermore, in rpAD brain lesions, SFPQ and p-tau showed extranuclear colocalization. Of note, association between SFPQ and tau-oligomers in rpAD brains suggests a possible role of SFPQ in oligomerization and subsequent misfolding of tau protein. In line with the findings from the human brain, our in vitro study showed that SFPQ is recruited into TIA-1-positive stress granules (SGs) after oxidative stress induction, and colocalizes with tau/p-tau in these granules, providing a possible mechanism of SFPQ dislocation through pathological SGs. Furthermore, the expression of human tau in vitro induced significant downregulation of SFPQ, suggesting a causal role of tau in the downregulation of SFPQ. The findings from the current study indicate that the dysregulation and dislocation of SFPQ, the subsequent DNA-related anomalies and aberrant dynamics of SGs in association with pathological tau represents a critical pathway which contributes to rapid progression of AD.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/patologia , Fator de Processamento Associado a PTB/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Citoplasma/metabolismo , Regulação para Baixo/fisiologia , Humanos , Camundongos Transgênicos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
3.
Prion ; 14(1): 95-108, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32138593

RESUMO

Cellular prion protein (PrPC) is a plasma membrane glycophosphatidylinositol-anchored protein and it is involved in multiple functions, including neuroprotection and oxidative stress. So far, most of the PrPC functional research is done in neuronal tissue or cell lines; the role of PrPC in non-neuronal tissues such as liver is only poorly understood. To characterize the role of PrPC in the liver, a proteomics approach was applied in the liver tissue of PrPC knockout mice. The proteome analysis and biochemical validations showed an excessive fat accumulation in the liver of PrPC knockout mice with a change in mRNA expression of genes linked to lipid metabolism. In addition, the higher Bax to Bcl2 ratio, up-regulation of tgfb1 mRNA expression in PrPC knockout mice liver, further showed the evidences of metabolic disease. Over-expression of PrPC in fatty acid-treated AML12 hepatic cell line caused a reduction in excessive intracellular fat accumulation; shows association of PrPC levels and lipid metabolism. Therefore, based on observation of excessive fat globules in the liver of ageing PrPC knockout mice and the reduction of fat accumulation in AML12 cell line with PrPC over-expression, the role of PrPC in lipid metabolism is described.


Assuntos
Metabolismo dos Lipídeos , Fígado/metabolismo , Proteínas Priônicas/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Adiposidade , Animais , Linhagem Celular , Eletroforese em Gel Bidimensional , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/genética , Masculino , Doenças Metabólicas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/metabolismo , Proteoma/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Triglicerídeos/metabolismo
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