Emerging role of RNA-binding proteins in sporadic and rapid progressive Alzheimer’s disease
by Neelam Younas
Date of Examination:2020-01-14
Date of issue:2020-04-07
Advisor:Prof. Dr. Inga Zerr
Referee:Prof. Dr. Thomas Meyer
Referee:Prof. Dr. Tiago Fleming Outeiro
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EnglishAlzheimer’s disease (AD) is the most prevalent cause of dementia. Typically, AD is characterized as a slow progressive dementia with an average disease duration of eight years. Recently, a rapidly progressive variant of Alzheimer’s disease (rpAD) was identified, in which patients exhibit a rapid cognitive decline and/or short disease duration (average of 4 years). It is known that spAD and rpAD share core neuropathological features, but unfortunately the altered molecular processes, which eventually lead to these variable rates of progression, remain elusive. To this end, we aimed to explore the emerging role of RNA-binding proteins (RBPs) in these two AD subtypes and in sporadic Creutzfeldt-Jakob disease (sCJD), another rapidly progressive form of dementia as well as control subjects. The proteomic investigation, in combination with several bioinformatic and computational approaches, highlighted quantitative and qualitative changes in the identified RNA-binding proteome in a disease-subtype-specific manner. Findings from the current study shows that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ) is dysregulated at both the protein and mRNA level in the frontal cortex of patients diagnosed with rpAD or sCJD as well as in the brains of 3xTg-AD mice. Co-immunofluorescence analysis in combination with confocal-laser scanning microscopy demonstrated nuclear depletion of SFPQ along with phospho-tau, particularly in cases of rapidly progressive AD. This nuclear depletion of both proteins was concomitantly associated with their cytoplasmic redistribution. Of note, association between SFPQ and tau in rpAD brain did not exclude the possible role of SFPQ in oligomerization and misfolding of tau protein. In the human brain, immunoreactivity of SFPQ co-localized with cytoplasmic TIA-1, which is a marker of stress granules. A similar translocation of SFPQ and phospho-tau into cytoplasmic TIA-1-positive stress granules was also obtained in cultured HeLa cells treated with sodium arsenite. Furthermore, the expression of human tau in vitro induced a significant reduction in SFPQ levels, suggesting a causal role of tau in downregulation of SFPQ. The findings from the current study indicate that dysregulated SFPQ in combination with pathological tau and aberrant dynamics of SGs represents an important pathway, which may contribute to the rapid progression of AD.
Keywords: RNA-binding proteins, rapidly progressive Alzheimer’s disease, SFPQ, stress granules, dislocation, 3xTg-mice.