NDLI: Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Akashiba, Hiroki Nishiyama, Nobuyoshi Matsuki, Norio Ikegaya, Yuji
Description	Author Affiliation: Akashiba H ( Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.)
Abstract	Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclin-dependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G(1) phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-d-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca(2+) and activation of calpain, a Ca(2+)-dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca(2+) and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	10
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2008-03-07
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cerebral Cortex Metabolism Corpus Striatum Cyclin-Dependent Kinase Inhibitor P27 Enzyme Inhibitors Toxicity G1 Phase Drug Effects Nitro Compounds Propionates Succinate Dehydrogenase Antagonists & Inhibitors Animals Calcium Signaling Calpain Cell Death Pathology Convulsants Cyclin-Dependent Kinases Huntington Disease Organ Specificity Phosphorylation RNA, Small Interfering Pharmacology Rats, Wistar Receptors, N-Methyl-D-Aspartate Biosynthesis Retinoblastoma Protein Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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