The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases

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 ER-resident 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 Alzheimer's disease, Parkinson's 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 stress-induced 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.