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Down‐regulation of Bcl‐2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum
Author(s) -
Zhang XingDing,
Wang Ye,
Wu JunChao,
Lin Fang,
Han Rong,
Han Feng,
Fukunaga Kohji,
Qin ZhengHong
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22152
Subject(s) - autophagy , programmed cell death , striatum , mitochondrion , microbiology and biotechnology , apoptosis , cytochrome c , biology , chemistry , biochemistry , neuroscience , dopamine
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. © 2009 Wiley‐Liss, Inc.