The homocysteine-inducible endoplasmic reticulum (ER) stress protein herp counteracts mutant α-synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins

Cherine Belal, Neema J. Ameli, Adam El kommos, Spencer Bezalel, Aziz M. Al'Khafaji, Mohamed R. Mughal, Mark P. Mattson, George A. Kyriazis, Björn Tyrberg, Sic L. Chan

Research output: Contribution to journalArticle

Abstract

Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases. The mechanisms that lead to ER stress and whereby ER stress contributes to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies. Here we show that knockdown of Herp (Homocysteine-inducible ER stress protein), an ER stress-inducible protein with an ubiquitin-like (UBL) domain, aggravates ER stress-mediated cell death induced by mutant a-synuclein (aSyn) that causes an inherited form of Parkinson's disease (PD). Functionally, Herp plays a role in maintaining ER homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca 2+ release channels. Deletion of the UBL domain or pharmacological inhibition of proteasomes abolishes the Herp-mediated stabilization of ER Ca 2+ homeostasis. Furthermore, knockdown or pharmacological inhibition of ER Ca 2+ release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca 2+ channels promotes a protracted ER stress with the consequent activation of ER stress-associated apoptotic pathways. Interestingly, sustained upregulation of ER stress markers and aberrant accumulation of ER Ca 2+ release channels were detected in transgenic mutant A53T-αSyn mice. Collectively, these data establish a causative link between impaired ER Ca 2+ homeostasis and chronic ER stress in the degenerative cascades induced by mutant aSyn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca 2+ homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca 2+-stabilizing action.

Original languageEnglish (US)
Article numberddr502
Pages (from-to)963-977
Number of pages15
JournalHuman Molecular Genetics
Volume21
Issue number5
DOIs
StatePublished - Mar 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Belal, C., Ameli, N. J., El kommos, A., Bezalel, S., Al'Khafaji, A. M., Mughal, M. R., Mattson, M. P., Kyriazis, G. A., Tyrberg, B., & Chan, S. L. (2012). The homocysteine-inducible endoplasmic reticulum (ER) stress protein herp counteracts mutant α-synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins. Human Molecular Genetics, 21(5), 963-977. [ddr502]. https://doi.org/10.1093/hmg/ddr502