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Effects of Ubiquilin 1 on the Unfolded Protein Response

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Abstract

Previous studies have implicated the unfolded protein response (UPR) in the pathogenesis of Alzheimer’s disease (AD). We previously reported that DNA variants in the ubiquilin 1 (UBQLN1) gene increase the risk for AD. Since UBQLN1 has been shown to play a role in the UPR, we assessed the effects of overexpression and downregulation of UBQLN1 splice variants during tunicamycin-induced ER stress. In addition to previously described transcript variants, TV1 and TV2, we identified two novel transcript variants of UBQLN1 in brain: TV3 (lacking exons 2–4) and TV4 (lacking exon 4). Overexpression of TV1–3, but not TV4 significantly decreased the mRNA induction of UPR-inducible genes, C/EBP homologous protein (CHOP), BiP/GRP78, and protein disulfide isomerase (PDI) during the UPR. Stable overexpression of TV1–3, but not TV4, also significantly decreased the induction of CHOP protein and increased cell viability during the UPR. In contrast, downregulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. These findings suggest that overexpression UBQLN1 transcript variants TV1–3, but not TV4, exert a protective effect during the UPR by attenuating CHOP induction and potentially increasing cell viability.

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Acknowledgements

This work was supported by the Extendicare Foundation, EVO grant 5772708 from Kuopio University Hospital, Finland, and the Finnish Academy (Mikko Hiltunen). We thank Petra Mäkinen for her excellent technical help.

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The authors have no actual or potential conflicts of interest.

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Authors and Affiliations

  1. Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA

    Alice Lu, Mikko Hiltunen, Donna M. Romano, Lars Bertram & Rudolph E. Tanzi

  2. Harvard Medical School, 114 16th St. C3009, Charlestown, MA, 02129-4404, USA

    Alice Lu & Rudolph E. Tanzi

  3. Department of Neurology, University Hospital, PO. Box 1627, 70211, Kuopio, Finland

    Mikko Hiltunen & Hilkka Soininen

  4. Department of Neurology, University of Kuopio, PO. Box 1627, 70211, Kuopio, Finland

    Mikko Hiltunen & Hilkka Soininen

  5. Alzheimer’s Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Bradley T. Hyman

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  1. Alice Lu
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  2. Mikko Hiltunen
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  3. Donna M. Romano
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Correspondence to Mikko Hiltunen or Rudolph E. Tanzi.

Additional information

A. Lu and M. Hiltunen contributed equally to this work.

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Lu, A., Hiltunen, M., Romano, D.M. et al. Effects of Ubiquilin 1 on the Unfolded Protein Response. J Mol Neurosci 38, 19–30 (2009). https://doi.org/10.1007/s12031-008-9155-6

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  • DOI: https://doi.org/10.1007/s12031-008-9155-6

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