The N-terminal Set-β Protein Isoform Induces Neuronal Death

Set-beta protein plays different roles in neurons, but the diversity of Set-beta neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-beta are altered in Alzheimer disease, cleavage of Set-beta leads to neuronal death after stroke, and the full-length Set-beta 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-beta 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-beta-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-beta transcript lacking the nuclear localization signal and demonstrated that the full-length (similar to 39-kDa) Set-beta is localized predominantly in the nucleus, whereas a shorter (similar to 25-kDa) Set-beta isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-beta cleavage product can induce neuronal death.