SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer's disease
| Autor: | Anna Siegert, Mathias Schmitz, Christine Stadelmann, Isidre Ferrer, Neelam Younas, Ayesha Zafar, Aneeqa Noor, Alexey Galkin, Olivier Andreoletti, Amandeep Singh Arora, Saima Zafar, Mohsin Shafiq, Inga Zerr |
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| Přispěvatelé: | German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), National University of Sciences and Technology [Islamabad] (NUST), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Ohio State University [Columbus] (OSU), Vavilov Institute of General Genetics, Russian Academy of Sciences [Moscow] (RAS), University Medical Center Göttingen (UMG), Institute of Neuropathology [Göttingen, Germany], Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Pathology and Experimental Therapeutics, University of Barcelona-IDIBELL, Bellvitge University Hospital [Barcelona, Spain], L’Hospitalet de Llobregat [Barcelona, Spain], Neurodegenerative Diseases Research Group (CIBERNED), Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Open Access funding provided by Project DEAL. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cytoplasm
Rapidly progressive Alzheimer’s disease [SDV]Life Sciences [q-bio] RNA-binding proteins RNA-binding protein medicine.disease_cause Creutzfeldt-Jakob Syndrome pathology [Alzheimer Disease] 0302 clinical medicine pathology [Brain] metabolism [Creutzfeldt-Jakob Syndrome] genetics [RNA-Binding Proteins] 3xTg mice 0303 health sciences Brain Human brain Rapidly progressive Alzheimer's disease Alzheimer's disease Cell biology medicine.anatomical_structure Stress granules metabolism [Alzheimer Disease] metabolism [PTB-Associated Splicing Factor] Tau protein Down-Regulation tau Proteins Mice Transgenic Biology metabolism [RNA-Binding Proteins] Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience Splicing factor Stress granule Downregulation and upregulation Alzheimer Disease medicine Dislocation Animals Humans ddc:610 PTB-Associated Splicing Factor metabolism [Cytoplasm] 030304 developmental biology Original Paper SFPQ Colocalization metabolism [tau Proteins] Malaltia d'Alzheimer physiology [Down-Regulation] metabolism [Brain] biology.protein RNA Neurology (clinical) 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Acta neuropathologica 140(3), 317-339 (2020). doi:10.1007/s00401-020-02178-y Dipòsit Digital de la UB Universidad de Barcelona Acta Neuropathologica Acta Neuropathologica, Springer Verlag, 2020, 140 (3), pp.317-339. ⟨10.1007/s00401-020-02178-y⟩ |
| ISSN: | 0001-6322 1432-0533 |
| DOI: | 10.1007/s00401-020-02178-y |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1007/s00401-020-02178-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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