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DENN/MADD/IG20 Alternative Splicing Changes and Cell Death in Alzheimer’s Disease

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Abstract

The potential effects of alternative splicing of death-domain expressing genes and neuronal death have not been determined in Alzheimer’s disease (AD). We analyzed DENN/MADD/IG20 (DMI), the complex of four splice variants. IG20 is known to be involved in cell death and the DENN/MADD splice variant (DM-SV) in cell survival in non-neural systems. DENN/MADD (DM) and DENN/MADD splice variant 2 were also included. Using SH-SY5Y human neuroblastoma cultures exposed to high concentrations of oligomeric Aβ peptides (oAβ) as a model for neuronal death, there was initially an increased ratio of DM-SV to IG20 (DM-SV/IG20) and knockdown of DMI SVs including DM-SV with antisense DNA then increased cell death. Cultures transfected with small interfering RNAs (siRNAs) specific to subsets of DMI SVs but sparing DM-SV increased the DM-SV/IG20 ratio resulting in a reduction of cell death in the presence of oAβ. Effects on cell survival of DM and DM SV2, the other two SVs expressed in the CNS, are less clear. Compared to normal controls, alternative splicing changes in the CNS of AD patients during disease progression resulted in altered ratios of all of the SVs in a pattern over an extended time that mirrored that of the cultures, and coincided with the accumulation of endogenous, dimeric Aβ (dAβ). Thus, DM-SV may be required for neuronal survival by protecting against oAβ neurotoxicity, and IG20 may contribute to selective neuronal vulnerability in AD.

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Acknowledgments

We thank Dr. Li Zhou and Dimitri Diaz and Lingling Li for technical support, Drs. Renny Feldman and Christian Pike for helpful discussions, Drs. Janet Moradian-Oldak and Yuwei Fan for assistance with AFM, and Susan Ou of the California Institute of Technology for generation of monoclonal antibodies. This work was supported in part by the USC Alzheimer’s Disease Research Center (AG05142), National Institute of Aging (AG018879) to CAM, and by NIA (AG00093), the John Douglas French Foundation, Elizabeth Lent, Analee and Bud Yorkshire to YM.

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Authors and Affiliations

  1. Department of Pathology, MCA-341A, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA, 90033, USA

    Yi Mo, Celia Williams & Carol A. Miller

  2. Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, CA, 90033, USA

    Carol A. Miller

  3. Program in Neuroscience, University of Southern California Keck School of Medicine, Los Angeles, CA, 90033, USA

    Carol A. Miller

  4. MERCK Global Clinical Development and Regulatory Affairs, Rahway, NJ, 07065, USA

    Yi Mo

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  1. Yi Mo
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Correspondence to Carol A. Miller.

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Mo, Y., Williams, C. & Miller, C.A. DENN/MADD/IG20 Alternative Splicing Changes and Cell Death in Alzheimer’s Disease. J Mol Neurosci 48, 97–110 (2012). https://doi.org/10.1007/s12031-012-9782-9

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  • DOI: https://doi.org/10.1007/s12031-012-9782-9

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