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

• Published in: Human molecular genetics Vol. 21; no. 5; pp. 963 - 977
• Main Authors: Belal, Cherine, Ameli, Neema J, El Kommos, Adam, Bezalel, Spencer, Al'Khafaji, Aziz M, Mughal, Mohamed R, Mattson, Mark P, Kyriazis, George A, Tyrberg, Bjorn, Chan, Sic L
• Format: Journal Article
• Language: English
• Published: 01-03-2012
• Subjects: Apoptosis; Calcium channels; Calcium homeostasis; Calcium release channels; Cell death; Endoplasmic reticulum; Movement disorders; Neurodegenerative diseases; Parkinson's disease; proteasomes; stress proteins; Synuclein; Transgenic mice
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr502

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 ( alpha Syn) 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 super(2+) release channels. Deletion of the UBL domain or pharmacological inhibition of proteasomes abolishes the Herp-mediated stabilization of ER Ca super(2+) homeostasis. Furthermore, knockdown or pharmacological inhibition of ER Ca super(2+) release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca super(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 super(2+) release channels were detected in transgenic mutant A53T- alpha Syn mice. Collectively, these data establish a causative link between impaired ER Ca super(2+) homeostasis and chronic ER stress in the degenerative cascades induced by mutant alpha Syn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca super(2+) homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca super(2+)-stabilizing action.