Article

Journal of Molecular Neuroscience

, Volume 38, Issue 1, pp 19-30

First online:

Effects of Ubiquilin 1 on the Unfolded Protein Response

  • Alice LuAffiliated withGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General HospitalHarvard Medical School
  • , Mikko HiltunenAffiliated withGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General HospitalDepartment of Neurology, University HospitalDepartment of Neurology, University of Kuopio Email author 
  • , Donna M. RomanoAffiliated withGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
  • , Hilkka SoininenAffiliated withDepartment of Neurology, University HospitalDepartment of Neurology, University of Kuopio
  • , Bradley T. HymanAffiliated withAlzheimer’s Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
  • , Lars BertramAffiliated withGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
  • , Rudolph E. TanziAffiliated withGenetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General HospitalHarvard Medical School Email author 

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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.

Keywords

UBQLN1 Ubiquilin 1 UPR Unfolded protein response CHOP C/EBP homologous protein PDI Protein disulfide isomerase BiP/GRP78 AD Alzheimer’s disease