Journal Article

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

Jae-Woong Chang, Hyunwoo Choi, Hyun-Ji Kim, Dong-Gyu Jo, Young-Jun Jeon, Jee-Yeon Noh, Woo Jin Park and Yong-Keun Jung

in Human Molecular Genetics

Volume 16, issue 3, pages 317-326
Published in print February 2007 | ISSN: 0964-6906
Published online December 2006 | e-ISSN: 1460-2083 | DOI:
Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin

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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-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. 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.

Journal Article.  5443 words.  Illustrated.

Subjects: Genetics and Genomics

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