title: Targeting ASK1 in ER stress-related neurodegenerative diseases.
abstract: The accumulation of malfolded proteins in the endoplasmic reticulum (ER) induces ER stress, leading to the disturbance of ER function. To restore ER function and ER homeostasis, cells possess a highly specific ER quality control system termed the unfolded protein response (UPR), which increases the capacity of protein folding and reduces the amount of malfolded proteins. In case of prolonged ER stress or malfunction of the UPR, apoptosis signaling is activated. ER stress-induced apoptosis has recently been implicated in the pathogenesis of various conformational diseases. Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase (MAP3K) family, is activated by ER stress and mediates apoptosis. Recent studies have shown that the ASK1 pathway is involved in ER stress-induced neuronal cell death and contributes to the pathogenesis of neurodegenerative diseases. In this review, we summarize the molecular mechanisms of the UPR and ER stress-induced apoptosis and the possible roles of ASK1 activation in neurodegenerative diseases.
authors.affiliation: The University of Tokyo, Graduate School of Pharmaceutical Sciences, Cell Signaling, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Homma
authors.forename: Kazumi
authors.initials: K
authors.lastname: Katagiri
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D013312:Stress, Physiological
chemical_list: D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human