RGD Reference Report - The homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp counteracts mutant alpha-synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins. - Rat Genome Database

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

Authors: Belal, C  Ameli, NJ  El Kommos, A  Bezalel, S  Al'Khafaji, AM  Mughal, MR  Mattson, MP  Kyriazis, GA  Tyrberg, B  Chan, SL 
Citation: Belal C, etal., Hum Mol Genet. 2012 Mar 1;21(5):963-77. doi: 10.1093/hmg/ddr502. Epub 2011 Nov 1.
RGD ID: 10047316
Pubmed: PMID:22045699   (View Abstract at PubMed)
PMCID: PMC3277305   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddr502   (Journal Full-text)

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 alpha-synuclein (alphaSyn) 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-alphaSyn 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 alphaSyn 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.



Gene Herpud1 homocysteine inducible ER protein with ubiquitin like domain 1 Rattus norvegicus
Gene Itpr1 inositol 1,4,5-trisphosphate receptor, type 1 Rattus norvegicus