Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, Wang X, Xia Q, Duong DM, Street C, Cantero G, Cheng D, Jones DR, Wu Z, Li Y, Diner I, Heilman CJ, Rees HD, Wu H, Lin L, Szulwach KE, Gearing M, Mufson EJ, Bennett DA, Montine TJ, Seyfried NT, Wingo TS, Sun YE, Jin P, Hanfelt J, Willcock DM, Levey A, Lah JJ, Peng J. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-7. PubMed.
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The University of Queensland
This is interesting also in the context of our finding that in the presence of tau the splicing factor SFPQ is relocalized from the nucleus to the cytoplasm.
References:
Ke Y, Dramiga J, Schütz U, Kril JJ, Ittner LM, Schröder H, Götz J. Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease. PLoS One. 2012;7(4):e35678. PubMed.
View all comments by Jürgen GötzMedical University of South Carolina
This is a truly exciting advance. While the small RNA world has captured the attention of the field, the global spicing failure is very novel and has been ignored since the days of KPI containing APP forms. It is curious that the authors saw a large increase in most (60 percent) of the MCI subjects tested, although only a relatively small fraction of them will end up getting AD. Does this mean that the deficit extends to other causes of MCI or that U1 protein dyshomeostais is an early and reversible defect?
View all comments by Kumar SambamurtiRutgers - New Jersey Medical School
This excellent paper brings back bittersweet memories from almost ten years ago, when we were captivated by the idea that RNA splicing in neurons could be altered in Alzheimer's by the availability of a C-terminal fragment of APP in the nucleus. In 2004, we proposed this notion in a paper that concluded that APP-specifically, a threonine-phosphorylated, C-terminal fragment (likely, AICD)-could regulate pre-mRNA splicing by localizing to the nuclear splicing factor compartment (SFC) [1].
The SFC is enriched in splicing factors (mostly SR proteins), snRNAs, and ribosomal proteins among others. It serves as storage and assembly site for the splicing machinery, regulating concentration and availability of splicing factors, and thus regulating pre-mRNA splicing [2, 3]. The SFC also contains transcription factors, and was proposed to play a role in regulating transcription [3].
The general belief at that time was that the C-terminal fragments of APP, in conjunction with the APP-binding protein Fe65, could regulate the transcription of AD-related genes [4-6]; less focus was given to their role in RNA splicing. Yet, the possibility that APP-derived polypeptides could participate in pre-mRNA splicing was–and still is-attractive to us. Our hypothesis on the dysregulation of pre-mRNA splicing in AD differs from that of Bai et al. Nevertheless, the idea that imbalanced APP metabolism leads to an excess of phosphorylated C-terminal fragment, and thus alters pre-mRNA splicing-as we thought-is compatible with the notion that AD-related conditions disrupt neuronal RNA processing. This in turn could play a role in AD pathogenesis, as Bai et al. now propose. Both lines of study are interesting, and need to be pursued.
References:
Muresan Z, Muresan V. A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment. Hum Mol Genet. 2004 Mar 1;13(5):475-88. PubMed.
Matera AG. Nuclear bodies: multifaceted subdomains of the interchromatin space. Trends Cell Biol. 1999 Aug;9(8):302-9. PubMed.
Misteli T. Cell biology of transcription and pre-mRNA splicing: nuclear architecture meets nuclear function. J Cell Sci. 2000 Jun;113 ( Pt 11):1841-9. PubMed.
Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell. 2002 Jul 12;110(1):55-67. PubMed.
Cao X, Südhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001 Jul 6;293(5527):115-20. PubMed.
Gao Y, Pimplikar SW. The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14979-84. PubMed.
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