• J. Neurosci. Res. · Dec 2009

    Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum.

    • Xing-Ding Zhang, Ye Wang, Jun-Chao Wu, Fang Lin, Rong Han, Feng Han, Kohji Fukunaga, and Zheng-Hong Qin.
    • Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
    • J. Neurosci. Res. 2009 Dec 1;87(16):3600-10.

    AbstractIn vivo administration of the mitochondrial inhibitor 3-nitropropionic acid (3-NP) produces striatal pathology mimicking Huntington's disease (HD). However, the mechanisms of cell death induced by metabolic impairment are not fully understood. Previous studies showed that 3-NP triggered p53-depedent autophagy activation and cell death. The present study investigated the contribution of the Bcl-2 signaling pathway to autophagy activation and cell death induced by 3-NP. Rat striatum was intoxicated with 3-NP by stereotaxic injection. 3-NP up-regulated the expression of the autophagic protein beclin 1 but down-regulated the expression of the antiapoptotic protein Bcl-2. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly inhibited the 3-NP-induced alterations in beclin 1 and Bcl-2 protein levels. Similarly, the 3-NP-induced decline in Bcl-2 was also prevented by the lysosomal inhibitor E64, indicating degradation of Bcl-2 by lysosomes. In agreement with the time course of 3-NP-induced cell death, an increase in the release of cytochrome c from mitochondria was observed. 3-MA also attenuated the 3-NP-induced release of cytochrome c. On the other hand, 3-NP-induced elevations in proapoptotic protein Bax and autophagic protein beclin 1 and LC3-II were significantly enhanced by the Bcl-2-specific inhibitor HA14-1. Furthermore, HA14-1 increased the release of cytochrome c and 3-NP-induced striatal damage. These results suggest that induction of autophagy leads to degradation of Bcl-2. Meanwhile, down-regulation of Bcl-2 amplifies autophagy activation and apoptotic signaling. Bcl-2 thus plays important roles in mitochondria dysfunction-induced apoptotic death of stritatal neurons by modulating both autophagic and apoptotic processes.Copyright 2009 Wiley-Liss, Inc.

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