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The Journal of Neuroscience, July 2, 2003, 23(13):5887-5896

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Alivin 1, a Novel Neuronal Activity-Dependent Gene, Inhibits Apoptosis and Promotes Survival of Cerebellar Granule Neurons

Tomio Ono, Naoko Sekino-Suzuki, Yoshiaki Kikkawa, Hiromichi Yonekawa, and Seiichi Kawashima

The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo 113-8613, Japan

Neurons require Ca²⁺-dependent gene transcription for their activity-dependent survival, the mechanisms of which have not been fully elucidated yet. Here, we demonstrate that a novel primary response gene, alivin 1 (ali1), is an activity-dependent gene and promotes survival of neurons. Sequence analyses reveal that rat, mouse, and human Ali1 proteins contain seven leucine-rich repeats, one IgC2-like loop and a transmembrane domain, and display homology to Kek and Trk families. Expression of ali1 mRNA in cultured cerebellar granule neurons is rigidly regulated by KCl and/or NMDA concentrations in the culture medium and tightly correlated to depolarization-dependent survival and/or NMDA-dependent survival of the granule neuron. ali1 mRNA expression was regulated at the transcriptional step by the Ca²⁺ influx through voltage-dependent L-type Ca²⁺ channels when the cells were stimulated by 25 mM KCl. Expression of ali1 mRNA in cultured cortical neurons was inhibited when their spontaneous electrical activity was blocked by tetrodotoxin. Thus, the expression is neuronal activity dependent. Overexpression of Ali1 in cerebellar granule neurons inhibited apoptosis that was induced by the medium containing 5 mM KCl. The addition of anti-Ali1 antiserum or the soluble putative extracellular Ali1 domain to the 25 mM KCl-supported culture inhibited the survival of the granule neuron. These results suggest that expression of ali1 promotes depolarization-dependent survival of the granule neuron. Mouse ali1 was mapped to a locus 55.3 cM from the centromere on chromosome 15 that is syntenic to positional candidate loci for familial Alzheimer's disease type 5 and Parkinson's disease 8 on human chromosome 12.

Key words: alivin; leucine-rich repeat; Ig superfamily; apoptosis; survival; activity-dependent; NMDA; depolarization; Alzheimer's disease; Parkinson's disease

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Received Sep. 5, 2002; revised May. 13, 2003; accepted May. 14, 2003.

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