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Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease

Yi-Chen Hsieh, Caiwei Guo, Hari K. Yalamanchili, Measho Abreha, Rami Al-Ouran, Yarong Li, Eric B. Dammer, James J. Lah, Allan I. Levey, David A. Bennett, Philip L. De Jager, Nicholas T. Seyfried, Zhandong Liu, Joshua M. Shulman
doi: https://doi.org/10.1101/514927
Yi-Chen Hsieh
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Caiwei Guo
2Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
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Hari K. Yalamanchili
3Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Measho Abreha
4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
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Rami Al-Ouran
3Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Yarong Li
5Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
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Eric B. Dammer
4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
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James J. Lah
6Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Allan I. Levey
6Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
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David A. Bennett
7Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
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Philip L. De Jager
8Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
9Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA
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Nicholas T. Seyfried
4Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
6Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Zhandong Liu
3Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
10Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
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Joshua M. Shulman
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
2Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
5Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
10Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
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  • For correspondence: Joshua.Shulman@bcm.edu
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SUMMARY

In Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.

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Posted January 09, 2019.
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Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease
Yi-Chen Hsieh, Caiwei Guo, Hari K. Yalamanchili, Measho Abreha, Rami Al-Ouran, Yarong Li, Eric B. Dammer, James J. Lah, Allan I. Levey, David A. Bennett, Philip L. De Jager, Nicholas T. Seyfried, Zhandong Liu, Joshua M. Shulman
bioRxiv 514927; doi: https://doi.org/10.1101/514927
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Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease
Yi-Chen Hsieh, Caiwei Guo, Hari K. Yalamanchili, Measho Abreha, Rami Al-Ouran, Yarong Li, Eric B. Dammer, James J. Lah, Allan I. Levey, David A. Bennett, Philip L. De Jager, Nicholas T. Seyfried, Zhandong Liu, Joshua M. Shulman
bioRxiv 514927; doi: https://doi.org/10.1101/514927

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