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Raj T, Li YI, Wong G, Humphrey J, Wang M, Ramdhani S, Wang YC, Ng B, Gupta I, Haroutunian V, Schadt EE, Young-Pearse T, Mostafavi S, Zhang B, Sklar P, Bennett DA, De Jager PL. Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility. Nat Genet. 2018 Nov;50(11):1584-1592. Epub 2018 Oct 8 PubMed.
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MRC Laboratory of Molecular Biology
This intriguing paper, which includes cases of Alzheimer’s disease, describes a genome-wide map of mRNA splicing variation in the aging prefrontal cortex. Interestingly, many differentially spliced sequences were found to be associated with the presence of neurofibrillary lesions. Some of the changes in splicing were also characteristic of cells that expressed phosphorylated tau. These findings, which need to be confirmed using a larger number of cell lines, suggest that elevated levels of tau can lead to splicing abnormalities.
It remains to be seen if the mechanisms behind the splicing changes in one brain region of end-stage Alzheimer’s disease were the same as those underlying the abnormal mRNA splicing observed following tau expression in iPS cells. Some of these changes might lead to the assembly of tau into filaments, which could in turn modify the splicing patterns of other mRNAs. It also remains to be seen if the splicing variation observed in Alzheimer’s disease was the cause or a consequence of the pathological changes. Its relevance for the neurodegenerative process remains to be established.
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