Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway

Abstract

Presenilin 1 (PS1) interacts with telencephalin (TLN) and the amyloid precursor protein via their transmembrane domain (Annaert, W.G., C. Esselens, V. Baert, C. Boeve, G. Snellings, P. Cupers, K. Craessaerts, and B. De Strooper. 2001. Neuron. 32:579–589). Here, we demonstrate that TLN is not a substrate for γ-secretase cleavage, but displays a prolonged half-life in PS1−/− hippocampal neurons. TLN accumulates in intracellular structures bearing characteristics of autophagic vacuoles including the presence of Apg12p and LC3. Importantly, the TLN accumulations are suppressed by adenoviral expression of wild-type, FAD-linked and D257A mutant PS1, indicating that this phenotype is independent from γ-secretase activity. Cathepsin D deficiency also results in the localization of TLN to autophagic vacuoles. TLN mediates the uptake of microbeads concomitant with actin and PIP2 recruitment, indicating a phagocytic origin of TLN accumulations. Absence of endosomal/lysosomal proteins suggests that the TLN-positive vacuoles fail to fuse with endosomes/lysosomes, preventing their acidification and further degradation. Collectively, PS1 deficiency affects in a γ-secretase–independent fashion the turnover of TLN through autophagic vacuoles, most likely by an impaired capability to fuse with lysosomes.

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

“…Intriguingly, cellular phenotypes in PIP 2 -compromised cells are reminiscent of those observed in cells expressing FADassociated presenilin mutations, e.g., ion channel and trafficking deficits (15). The potential role of presenilin in PIP 2 metabolism can be further evidenced by occurrence of PS1 in PIP 2 -enriched subcellular compartments, including lipid rafts (44), phagocytic cups (19), lamellipodia (45), and adherent junctions (18). Thus, our study raises the possibility that PIP 2 may play a key role in the multiple cellular defects associated with presenilin FAD mutations.…”

“…Two of the most consistent cellular changes associated with both PS1 and PS2 FAD-associated mutations include ion channel dysfunction, such as defects in capacitative Ca 2ϩ entry (CCE) (16,17) and membrane trafficking defects, including diminished cell surface delivery of APP (15,(19)(20)(21). These A␤42-independent cellular changes may also contribute to the onset and/or neuropathological characteristics of presenilindependent FAD (22).…”

Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation

“…Reports by Esselens et al (20) and Wilson et al (21) implicated a role of PS1 in the turnover of telencephalin and ␣-and ␤-synucleins, respectively. They showed that these molecules accumulate in degradative organelles resembling autophagosomes in PS1-null neurons, but not by ␥-secretase inhibitor treatment (20,21). Thus, this activity is likely mediated through a ␥-secretase independent mechanism.…”

Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved

“…Other proposed activities of PS that are independent of ␥-secretase include a role in transport of several membrane proteins (34)(35)(36), autophagy and protein degradation (37,38), or act as a scaffold in Erk activation (39,40). However, the dominant phenotype caused by loss of Notch signaling (41)(42)(43) severely limits the ability to identify and interrogate the physiological relevance of the entire spectrum of PS functions.…”