Journal Article

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 and Sic L. Chan

in Human Molecular Genetics

Volume 21, issue 5, pages 963-977
Published in print March 2012 | ISSN: 0964-6906
Published online November 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr502
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

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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 α-synuclein (αSyn) 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 Ca2+ release channels. Deletion of the UBL domain or pharmacological inhibition of proteasomes abolishes the Herp-mediated stabilization of ER Ca2+ homeostasis. Furthermore, knockdown or pharmacological inhibition of ER Ca2+ release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca2+ 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 Ca2+ release channels were detected in transgenic mutant A53T-αSyn mice. Collectively, these data establish a causative link between impaired ER Ca2+ homeostasis and chronic ER stress in the degenerative cascades induced by mutant αSyn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca2+ homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca2+-stabilizing action.

Journal Article.  9066 words.  Illustrated.

Subjects: Genetics and Genomics

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