Mixed Messages: mRNA Splicing Errors May Promote Alzheimer’s

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16/10/2018

Many genetic variants predispose to Alzheimer’s disease, but exactly how remains a mystery. In the October 8 Nature Genetics, researchers led by Philip De Jager at Columbia University and Towfique Raj at Icahn School of Medicine at Mount Sinai, both in New York, and David Bennett at Rush University in Chicago implicate mRNA splicing. The authors analyzed gene-expression patterns in 450 postmortem brains from AD patients and controls. The amount of plaques and tangles correlated with alternative and mis-splicing of a specific set of transcripts. Many of these genes had not been associated with AD previously. The authors re-created some of the splicing changes by exposing cultured cells to high levels of phosphorylated tau, suggesting pathology bungles RNA processing. In a separate analysis, other splicing patterns correlated with genetic variants, in particular those in the known AD genes CLU, PICALM, and PTK2B. “For those genes, I think we’ve identified the proximal mechanism by which they alter cell function and eventually lead to dementia,” De Jager told Alzforum.