Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis

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We have previously developed a fly model for IBMPFD (inclusion body myopathy with Paget disease and frontotemporal dementia) and demonstrated that specific mutations in VCP gene, a highly conserved ATPase, cause muscle and neuron degeneration by depleting cellular ATP level. Using this model, we show that expression of Derlin-1, an ER membrane protein capable of directly interacting with VCP, restores the normal cellular ATP level and suppresses IBMPFD-like neurodegeneration. As Derlin-1 expression can be induced by tunicamycin (an antibiotic) in experimental systems, our findings may yield new therapeutic strategies for VCP-linked diseases. In addition, we have obtained important insights regarding Derlin-1 function under physiological conditions. ER stress, caused by accumulation of improperly folded proteins, results in increased Derlin-1 expression, which is important for ER stress-induced cell death. We propose that Derlin-1 promotes ER homeostasis through multiple mechanisms. In addition to cooperating with VCP to extract improperly folded proteins from the ER, elevated Derlin-1 expression removes cells suffering from irreparable ER stress, thus preventing these damaged cells from further harming the organisms.

Vyšlo v časopise: Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004675
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004675

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