The Down syndrome (DS) candidate region gene 1 (DSCR1) is localized near DS critical region on chromosome 21 and is overexpressed in the brains of DS patients. Although DSCR1 was known for a modulator of calcineurin, the overexpression of DSCR1 is thought to play a role in neuronal cell death. Zinc, one of the most abundant transition metals in the brain, may also contribute to selective neuronal cell death when present in excessive amounts. In the present study, we investigated the effect of DSCR1 overexpression on zinc-induced cell death in hippocampal neuroprogenitor cells. The overexpression of DSCR1 caused apoptotic cell death without an apparent formation of intracellular protein inclusions. Upon exposure to zinc, soluble DSCR1 levels were significantly decreased and insoluble levels were enhanced to a similar extent, which were partially caused by the zinc-induced inhibition of proteasomal activity and a consequently diminished degradation of DSCR1. Furthermore, zinc treatment induced the formation of nuclear DSCR1 aggregates, which blocked zinc-induced cell death. These findings indicate that, although the up-regulation of DSCR1 levels exerts a cytotoxic effect, the addition of zinc leads to the formation of cytoprotective nuclear aggregates in neuronal cells.
Bibliographical noteFunding Information:
The authors thank S. de la Luna and B.A. Rothermel for generously providing plasmids and H S. Cho and Y. J. Oh for their helpful discussions and technical assistance. We are also grateful to the members of the K.C. Chung laboratory for their help and discussions. This study was supported by a grant from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea (M103KV010002-03K2201-00600 to K.C.C.), by Basic Science Research Grant from the Korea Research Foundation (KRF2003-015-C00527 to K.C.C.), by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050181 and A060440 to K.C.C.), and by Basic Research Grant from the Korea Science and Engineering Foundation (R01-2004-000-10673-0 to K.C.C.). It was also partly supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2004-005-E00017 to K.C.C).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cellular and Molecular Neuroscience
- Cell Biology