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000153365 1001_ $$aYounas, Neelam$$b0
000153365 245__ $$aSFPQ and Tau: critical factors contributing to rapid progression of Alzheimer's disease.
000153365 260__ $$aHeidelberg$$bSpringer$$c2020
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000153365 520__ $$aDysfunctional 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.
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000153365 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000153365 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000153365 650_2 $$2MeSH$$aAnimals
000153365 650_2 $$2MeSH$$aBrain: metabolism
000153365 650_2 $$2MeSH$$aBrain: pathology
000153365 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: metabolism
000153365 650_2 $$2MeSH$$aCytoplasm: metabolism
000153365 650_2 $$2MeSH$$aDown-Regulation: physiology
000153365 650_2 $$2MeSH$$aHumans
000153365 650_2 $$2MeSH$$aMice, Transgenic
000153365 650_2 $$2MeSH$$aPTB-Associated Splicing Factor: metabolism
000153365 650_2 $$2MeSH$$aRNA-Binding Proteins: genetics
000153365 650_2 $$2MeSH$$aRNA-Binding Proteins: metabolism
000153365 650_2 $$2MeSH$$atau Proteins: metabolism
000153365 7001_ $$0P:(DE-2719)9000358$$aZafar, Saima$$b1$$eCorresponding author$$udzne
000153365 7001_ $$0P:(DE-2719)9000295$$aShafiq, Mohsin$$b2$$udzne
000153365 7001_ $$0P:(DE-2719)9001208$$aNoor, Aneeqa$$b3$$udzne
000153365 7001_ $$0P:(DE-2719)9000764$$aSiegert, Anna$$b4$$udzne
000153365 7001_ $$0P:(DE-2719)9000012$$aArora, Amandeep Singh$$b5$$udzne
000153365 7001_ $$aGalkin, Alexey$$b6
000153365 7001_ $$aZafar, Ayesha$$b7
000153365 7001_ $$0P:(DE-2719)9000287$$aSchmitz, Matthias$$b8$$udzne
000153365 7001_ $$0P:(DE-HGF)0$$aStadelmann, Christine$$b9
000153365 7001_ $$aAndreoletti, Olivier$$b10
000153365 7001_ $$aFerrer, Isidre$$b11
000153365 7001_ $$0P:(DE-2719)2000058$$aZerr, Inga$$b12$$eLast author$$udzne
000153365 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-020-02178-y$$gVol. 140, no. 3, p. 317 - 339$$n3$$p317 - 339$$tActa neuropathologica$$v140$$x1432-0533$$y2020
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