[Involvement of unfolded protein responses in neurodegeneration].
Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
Kudo
Takashi
T
Department of Clinical Neuroscience and Psychiatry, Osaka Universit Graduate School of Medicine, 2-2, Yamadaoka, Suita, 565-0871 Japan.
D051702:Activating Transcription Factor 6; D000544:Alzheimer Disease / Q000209:etiology; D017209:Apoptosis; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000209:etiology*; D053764:Presenilin-1; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction; D013312:Stress, Physiological / Q000503:physiopathology*; D014157:Transcription Factors / Q000502:physiology; D019892:eIF-2 Kinase / Q000502:physiology
D051702:Activating Transcription Factor 6; D053454:Caspase 12; D020169:Caspases; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D008565:Membrane Proteins; D018832:Molecular Chaperones; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C508853:PSEN1 protein, human; C403982:ERN2 protein, human; C506444:CASP12 protein, human