TY - JOUR
T1 - Critical role of lysosome and its associated protein cathepsin D in manganese-induced toxicity in cultured midbrain astrocyte
AU - Fan, Xiaolan
AU - Luo, Guangrui
AU - Yang, Dehua
AU - Ming, Ming
AU - Liu, Hongmei
AU - Pu, Pu
AU - Le, Weidong
N1 - Funding Information:
This work was supported by the National Nature Science Foundation of China (No. 30730096), the National Basic Research Program of China from Chinese Science & Technology Commission (2007CB947904), and the Chinese Science and Technology Commission (863 project 2007AA02Z460).
PY - 2010/1
Y1 - 2010/1
N2 - Astrocyte is considered to be the initial target in manganese neurotoxicity; however, the ultra structure changes in the cells and the mechanism underlying the manganese-induced toxicity are still unclear. In this study, we conducted several assays in cultured midbrain astrocyte to determine the role of mitochondria, lysosome and its associated protein cathepsin D in the manganese-induced toxicity. We found that a mixed form of cell death in the manganese treated astrocyte. During the process of cell death, we detected extensive cytoplasmic vacuolation, mitochondrial swelling, and increased number and membrane permeability of lysosomes in the manganese treated astrocyte. Furthermore, we documented that after exposed to manganese, the Bax protein level in the astrocyte was increased, and its cellular distribution was significantly translocated from cytosol to mitochondria and lysosomes. Moreover, we demonstrated that manganese treatment caused significant increase of lysosomal enzyme cathepsin D, and pretreatment with cathepsin D inhibitor pepstatin A increased the apoptotic cell death. Collectively, our study suggests that different forms of cell death are involved in manganese-induced toxicity in the cultured midbrain astrocyte, and lysosome and its associated protein cathepsin D play a critical role in the pathological process. These results may shed new light on the mechanism of manganese exposure related neurological disorders.
AB - Astrocyte is considered to be the initial target in manganese neurotoxicity; however, the ultra structure changes in the cells and the mechanism underlying the manganese-induced toxicity are still unclear. In this study, we conducted several assays in cultured midbrain astrocyte to determine the role of mitochondria, lysosome and its associated protein cathepsin D in the manganese-induced toxicity. We found that a mixed form of cell death in the manganese treated astrocyte. During the process of cell death, we detected extensive cytoplasmic vacuolation, mitochondrial swelling, and increased number and membrane permeability of lysosomes in the manganese treated astrocyte. Furthermore, we documented that after exposed to manganese, the Bax protein level in the astrocyte was increased, and its cellular distribution was significantly translocated from cytosol to mitochondria and lysosomes. Moreover, we demonstrated that manganese treatment caused significant increase of lysosomal enzyme cathepsin D, and pretreatment with cathepsin D inhibitor pepstatin A increased the apoptotic cell death. Collectively, our study suggests that different forms of cell death are involved in manganese-induced toxicity in the cultured midbrain astrocyte, and lysosome and its associated protein cathepsin D play a critical role in the pathological process. These results may shed new light on the mechanism of manganese exposure related neurological disorders.
KW - Apoptosis
KW - Cathepsin D
KW - Lysosomes
KW - Manganese
KW - Paraptosis
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U2 - 10.1016/j.neuint.2009.11.001
DO - 10.1016/j.neuint.2009.11.001
M3 - Article
C2 - 19913584
AN - SCOPUS:77149142602
SN - 0197-0186
VL - 56
SP - 291
EP - 300
JO - Neurochemistry International
JF - Neurochemistry International
IS - 2
ER -