Missorting of the dendritic cell adhesion molecule telencephalin in presenilin-deficient neurons

Presenilin deficiency abrogates gamma-secretase cleavage, thereby preventing the release of the amyloid peptide from the beta-clipped APP fragment or the notch intracellular domain. The presenilins are therefore implicated in such diverse processes as the neuro degeneration in Alzheimer's disease and the regulation of Notch signaling. The question remains whether other type I transmembrane proteins or pathways are subject to presenilin-mediated proteolysis. While the two aspartate residues in presenilin likely are essential for a functional gamma-secretase complex, the highly conserved carboxyterminal tail also appears to be important for presenilin function. Therefore we screened a double hybrid library with a short presenilin I carboxyterminal fragment as a bait. We identified a type I transmembrane protein that belongs to the family of intercellular cell adhesion molecules, telencephalin. Telencephalin is exclusively expressed in neurons of the telencephalic region, where it is abundantly expressed at the somatodendritic plasmamembrane. Functionally, telencephalin is, like notch, involved in neurite outgrowth. Interestingly, telencephalin is also involved in long-term potentiation. We confirmed the presenilin 1/telencephalin interaction using two other independent approaches. Finally, functional evidence for the physiological relevance of this interaction comes from the observation that telencephalin becomes mislocalized in differentiated hippocampal neurons. Further research into the telencephalin and presenilin 1 interaction may shed some light on the way presenilin I influences the processing of other type I transmembrane proteins, such as APP and Notch.