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

    Authors

    C. Belal; N. J. Ameli; A. El Kommos; S. Bezalel; A. M. Al'Khafaji; M. R. Mughal; M. P. Mattson; G. A. Kyriazis; B. Tyrberg;S. L. Chan

    Comments

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    Abbreviated Journal Title

    Hum. Mol. Genet.

    Keywords

    ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; RYANODINE; RECEPTOR; SUBSTANTIA-NIGRA; CORTICAL-NEURONS; NEUROTOXIN MODEL; DEGRADATION; APOPTOSIS; DEATH; Biochemistry & Molecular Biology; Genetics & Heredity

    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 -synuclein (Syn) that causes an inherited form of Parkinsons 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-Syn 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 Syn 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.

    Journal Title

    Human Molecular Genetics

    Volume

    21

    Issue/Number

    5

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    963

    Last Page

    977

    WOS Identifier

    WOS:000300242000001

    ISSN

    0964-6906

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