Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease

Ke, Yazi, Dramiga, Joe, Schütz, Ulrich, Kril, Jillian J., Ittner, Lars M., Schröder, Hannsjörg and Götz, Jürgen (2012) Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease. PloS One, 7 4: 1-8. doi:10.1371/journal.pone.0035678

Author Ke, Yazi
Dramiga, Joe
Schütz, Ulrich
Kril, Jillian J.
Ittner, Lars M.
Schröder, Hannsjörg
Götz, Jürgen
Title Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-04-25
Sub-type Article (original research)
DOI 10.1371/journal.pone.0035678
Open Access Status DOI
Volume 7
Issue 4
Start page 1
End page 8
Total pages 8
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted abstract
Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.
Keyword Amyotrophic lateral sclerosis
RNA-splicing factor
Transgenic mice
Binding protein
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 25 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 0 times in Scopus Article
Google Scholar Search Google Scholar
Created: Wed, 26 Feb 2014, 08:20:05 EST by System User on behalf of Queensland Brain Institute