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Human Molecular Genetics Advance Access originally published online on December 22, 2006
Human Molecular Genetics 2007 16(3):317-326; doi:10.1093/hmg/ddl466
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin

Jae-Woong Chang1,3, Hyunwoo Choi3, Hyun-Ji Kim1, Dong-Gyu Jo2, Young-Jun Jeon3, Jee-Yeon Noh1,3, Woo Jin Park1 and Yong-Keun Jung3,*

1 Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, 2 College of Pharmacy, Sungkyunkwan University, Suwon, Korea and 3 School of Biological Science/Bio-MAX Institute, Seoul National University, Shillim-Dong, Seoul 151-747, Korea

* Correspondence should be addressed. Tel: +82 28830486; Fax: +82 28872692; Email: ykjung{at}snu.ac.kr

Received December 8, 2006; Accepted December 9, 2006

Calsenilin/DREAM/KChIP3, a neuronal Ca2+-binding protein, has multifunctions in nucleus and cytosol. Here, we identified CLN3 as a calsenilin-binding partner whose mutation or deletion is observed in Batten disease. In vitro binding and immunoprecipitation assays show that calsenilin interacts with the C-terminal region of CLN3 and the increase of Ca2+ concentration in vitro and in cells causes significant dissociation of calsenilin from CLN3. Ectopic expression of CLN3 or its deletion mutant containing only the C-terminus (153–438) and capable of binding to calsenilin suppresses thapsigargin or A23187 [GenBank] -induced death of neuronal cells. In contrast, CLN3 deletion mutant containing the N-terminus (1–153) or (1–263), which is frequently found in Batten disease, induces the perturbation of Ca2+ transient and fails to inhibit the cell death. In addition, the expression of calsenilin is increased in the brain tissues of CLN3 knock-out mice and SH-SY5Y/CLN3 knock-down cells. Down-regulation of CLN3 expression sensitizes SH-SY5Y cells to thapsigargin or A23187. [GenBank] However, additional decrease of calsenilin expression rescues the sensitivity of SH-SY5Y/CLN3 knock-down cells to Ca2+-mediated cell death. These results suggest that the vulnerability of CLN3 knock-out or CLN3 deletion (1–153)-expressing neuronal cells to Ca2+-induced cell death may be mediated by calsenilin.


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