Figure 1. Immunofluorescent cell staining for GAPDH. Siah drives GAPDH to the nucleus via its nuclear localization signal (NLS). After translocation to the nucleus, GAPDH activates p300/CBP, which in turn stimulates p53 transcriptional activity. Blue, nucleus; red, GAPDH. | Mechanisms of Neuronal Cell Death: Link to Chromatin Remodeling Efforts to prevent neurodegeneration in disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and stroke have proceeded along two pathways: One involves identifying the fundamental molecular causes of these diseases, even though curative therapy may not follow directly (such as in the case of Huntington’s disease, where the molecular causation is established). Alternatively, mechanisms of cell death may be examined, which may lead to agents that prevent neurodegeneration without knowing the specific disease etiology. Here we focus on a general cascade of neurodegeneration, oxidative stress-induced programmed cell death, and agents that block the cascade. We have discovered novel death signaling via glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH was merely believed to be a housekeeping molecule in a classic glycolytic pathway, but now it is recognized as a multifunctional protein. Specific modification of GAPDH by nitric oxide and/or reactive oxygen species is the trigger of the death cascade in which the modified GAPDH translocates to the nucleus, where it disturbs histone modifications and gene transcription. In a representative cascade downstream of nuclear GAPDH, p300/CBP is activated by GAPDH. Extending from the GAPDH death cascade, we are currently interested in how cellular stresses can impact chromatin remodeling, especially in the context of neuropsychiatric disorders, such as Huntington’s disease and schizophrenia. We have also reported that a neuroprotective agent, deprenyl, blocks this cascade and displays neuroprotection. Thus, further study of this novel death cascade would contribute to understanding mechanisms of neurodegeneration as well as exploration of therapeutic strategies for neurodegenerative conditions. We have recently found several deprenyl structural analogues that display much stronger potency of blocking the GAPDH death cascade than deprenyl. We hope that this clue may open a novel opportunity to develop strategies for neuroprotection. | |
Figure 2. Genetic deletion of p53 diminishes neurodegeneration in the fly models for Huntington’s disease. Representative photomicrographs of ommatidia are shown. wt (wild-type), p53 (p53 null), Htt (Huntington’s disease model expressing mutant Huntingtin), Htt;p53 (Huntington’s disease model under p53 null condition). | ||
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