SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

被引：0

作者：

Neelam Younas

Saima Zafar

Mohsin Shafiq

Aneeqa Noor

Anna Siegert

Amandeep Singh Arora

Alexey Galkin

Ayesha Zafar

Mathias Schmitz

Christine Stadelmann

Olivier Andreoletti

Isidre Ferrer

Inga Zerr

机构：

[1] University Medical Center Göttingen and the German Center for Neurodegenerative Diseases (DZNE),Department of Neurology

[2] National University of Sciences and Technology (NUST),Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering (SMME)

[3] University Medical Center Hamburg-Eppendorf,Institute of Neuropathology

[4] The Ohio State University,Institute for Behavioral Medicine Research

[5] St. Petersburg Branch,College of Medicine Center for Pharmacogenomics

[6] Vavilov Institute of General Genetics,Institute of Neuropathology

[7] The Ohio State University,Department of Pathology and Experimental Therapeutics

[8] University Medical Center,undefined

[9] UMR INRA ENVT 1225- Interactions Hôte Agent Pathogène–École Nationale Vétérinaire de Toulouse,undefined

[10] University of Barcelona,undefined

[11] Bellvitge University Hospital-IDIBELL,undefined

[12] CIBERNED,undefined

[13] Hospitalet de Llobregat,undefined

来源：

Acta Neuropathologica | 2020年 / 140卷

关键词：

RNA-binding proteins; Rapidly progressive Alzheimer’s disease; SFPQ; Stress granules; Dislocation; 3xTg mice;

D O I：

暂无

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学科分类号：

摘要：

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.

引用

页码：317 / 339

页数：22