The N-terminal Set-beta Protein Isoform Induces Neuronal Death JOURNAL OF BIOLOGICAL CHEMISTRY Trakhtenberg, E. F., Morkin, M. I., Patel, K. H., Fernandez, S. G., Sang, A., Shaw, P., Liu, X., Wang, Y., Mlacker, G. M., Gao, H., Velmeshev, D., Dombrowski, S. M., Vitek, M. P., Goldberg, J. L. 2015; 290 (21): 13417-13426

Abstract

Set-ß protein plays different roles in neurons, but the diversity of Set-ß neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-ß are altered in Alzheimer disease, cleavage of Set-ß leads to neuronal death after stroke, and the full-length Set-ß regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-ß isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-ß-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-ß transcript lacking the nuclear localization signal and demonstrated that the full-length (~39-kDa) Set-ß is localized predominantly in the nucleus, whereas a shorter (~25-kDa) Set-ß isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-ß cleavage product can induce neuronal death.

View details for DOI 10.1074/jbc.M114.633883

View details for Web of Science ID 000354975700037

View details for PubMedID 25833944

View details for PubMedCentralID PMC4505589