The ASK1-MAP Kinase Signaling in ER Stress and Neurodegenerative Diseases
Yusuke Sekine, Kohsuke Takeda and Hidenori Ichijo
Affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The Universityof Tokyo, and CREST, Japan Science and Technology Corporation, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen induces ER stress. ER stress triggers the unfolded protein response (UPR), which includes the attenuation of general protein synthesis and the transcriptional activation of the genes encoding ERresident chaperones and molecules involved in the ER-associated degradation (ERAD). The UPR coordinately reduces ER stress by restoration of the protein-folding capacity of the ER. However, severe and/or prolonged ER stress eventually leads cells to apoptosis. Several lines of evidence suggest that ER stress-induced apoptosis plays critical roles in the pathogenesis of neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPKKK family that constitutes the JNK and p38 MAP kinase (MAPK) cascades, is activated by physiological and cytotoxic stresses and induces various stress responses including apoptosis. Recent studies have shown that the ASK1-MAPK cascades are involved in ER stressinduced apoptosis and in the neuronal cell death in some model systems of neurodegenerative diseases. This review highlights the current understanding of regulatory mechanisms of ASK1 with a special focus on the ER stress-dependent and -independent neuronal cell death in the context of neurodegenerative diseases.
Keywords: DNA repair, endoplasmic reticulum (ER), intracellular stresses, TNF receptor superfamily, apoptosis
Rights & PermissionsPrintExport