Introduction

 The endoplasmic reticulum (ER) is an organelle in which secretory and transmembrane proteins, as well as the resident proteins of the secretory pathway, are synthesized, folded, or modified. Perturbations in the efficiency of protein folding result in the accumulation of unfolded or misfolded proteins in the ER. For example, physiological or pharmacological conditions such as disturbance of calcium homeostasis, expression of mutated proteins, or ischemic insults, induce accumulation of these client proteins. These conditions, that are collectively termed ER stress, have the potential to induce cellular damage. Excessive or long-term stress in the ER causes apoptosis involving activation of caspases and stress kinases including Ask1 and JNK. The ER also contains specific signaling and effector mechanisms that sense and deal with accumulation of unfolded proteins. Major adaptive programs include the transcriptional induction of ER molecular chaperones, translational attenuation, and degradation of unfolded proteins. This defense system is conserved throughout yeast to higher eukaryotes, and termed the unfolded protein response (UPR). Research over the past several years has led to a detailed understanding of the major pathways of the UPR and death signaling induced by ER stress (Fig.1).


Fig.1

  Many neurodegenerative disorders have common pathological features; insoluble or malfolded proteins aggregate and are deposited in the neurons or matrix of the central nervous system. These proteins are inherently cytotoxic and cause neuronal damage. Recent studies have implicated the failure of the UPR in some neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. ER stress can be also provoked by a variety of pathophysiological conditions, such as in many recessively-inherited genetic diseases that are due to loss-of-function mutations, or protein-folding mutations that interfere with cellular processes, resulting in a gain of function and a dominant pattern of inheritance. To develop therapeutic strategies for these diseases, further insight into ER stress and its stress response is needed.

  In our laboratory, we investigate detailed signaling pathway of the UPR regulated in varieties of cell types, and particularly focus on the functions of transmembrane transcription factors resident in the ER such as OASIS (old astrocyte specifically induced substance) or BBF2H7, those are newly determined as ER stress transducers that may function in a tissue- or cell type-specific manner.

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Department of Biochemistry,
Graduate School of Biomedical & Health Sciences,
Hiroshima University

1-2-3 Kasumi, Minami-ku, Hiroshima,
734-8553Japan
TEL:81-82-257-5130 FAX:81-82-257-5134