Critical role of lysosome and its associated protein cathepsin D in manganese-induced toxicity in cultured midbrain astrocyte.
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.
Fan
Xiaolan
X
The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
Luo
Guangrui
G
Yang
Dehua
D
Ming
Ming
M
Liu
Hongmei
H
Pu
Pu
P
Le
Weidong
W
D001253:Astrocytes / Q000187:drug effects*; D002402:Cathepsin D / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D008345:Manganese / Q000633:toxicity*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects*
D008345:Manganese; D002402:Cathepsin D