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Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum.
J Neurosci Res. 2009 Dec; 87(16):3600-10.JN

Abstract

In 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.

Authors+Show Affiliations

Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19565656

Citation

Zhang, Xing-Ding, et al. "Down-regulation of Bcl-2 Enhances Autophagy Activation and Cell Death Induced By Mitochondrial Dysfunction in Rat Striatum." Journal of Neuroscience Research, vol. 87, no. 16, 2009, pp. 3600-10.
Zhang XD, Wang Y, Wu JC, et al. Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. J Neurosci Res. 2009;87(16):3600-10.
Zhang, X. D., Wang, Y., Wu, J. C., Lin, F., Han, R., Han, F., Fukunaga, K., & Qin, Z. H. (2009). Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. Journal of Neuroscience Research, 87(16), 3600-10. https://doi.org/10.1002/jnr.22152
Zhang XD, et al. Down-regulation of Bcl-2 Enhances Autophagy Activation and Cell Death Induced By Mitochondrial Dysfunction in Rat Striatum. J Neurosci Res. 2009;87(16):3600-10. PubMed PMID: 19565656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. AU - Zhang,Xing-Ding, AU - Wang,Ye, AU - Wu,Jun-Chao, AU - Lin,Fang, AU - Han,Rong, AU - Han,Feng, AU - Fukunaga,Kohji, AU - Qin,Zheng-Hong, PY - 2009/7/1/entrez PY - 2009/7/1/pubmed PY - 2010/1/6/medline SP - 3600 EP - 10 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 87 IS - 16 N2 - In 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. SN - 1097-4547 UR - https://www.unboundmedicine.com/medline/citation/19565656/Down_regulation_of_Bcl_2_enhances_autophagy_activation_and_cell_death_induced_by_mitochondrial_dysfunction_in_rat_striatum_ L2 - https://doi.org/10.1002/jnr.22152 DB - PRIME DP - Unbound Medicine ER -