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RNA Binding Proteins and Alzheimer’s Disease

Benjamin Wolozin, M.D., Ph.D.
Boston University School of Medicine

Results from a new mouse study, funded in part by NIEHS, showed that RNA binding proteins likely play a key role in the development of Alzheimer’s disease. The new findings reveal potential new therapeutic targets for the disease.

The brains of people with Alzheimer’s disease exhibit neurofibrillary tangles, or abnormal accumulations of the protein tau. The tangles are thought to injure neurons in a way that may lead to dementia. Using cultured cells, the researchers previously showed that reducing levels of an RNA-binding protein known as T-cell intracellular antigen 1 (TIA1) led to decreased tau accumulation. RNA-binding proteins help form the RNA-protein complexes that are important for DNA replication and regulating gene expression and RNA metabolism.

Building on the previous work, the researchers studied mice that modeled Alzheimer’s disease by accumulating tau in the brain. In these mice, reducing levels of TIA1 protected against neurodegeneration and prolonged survival although neurofibrillary tangles still increased. The team observed that reducing TIA1 decreased the amount of small tau clumps and increased the proportion of large tau clumps that generated neurofibrillary tangles and were less toxic. The study provided evidence that TIA1 plays a key role in mediating the toxicity of tau and suggest that RNA-binding proteins direct the pathway of tau aggregation and the neurodegeneration that follows. The new findings open many new therapeutic targets for exploration.

Citation: Apicco DJ, Ash PEA, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B. 2018. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci 21(1):72-80.

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