The job description of presenilins (PS) in the business of neuron health and disease may be getting more complicated. Besides their role—as the catalytic core of γ-secretase—in amyloid-β (Aβ) peptide production, these proteins also regulate the phosphorylation of tau via their effects on the PI3 kinase/Akt/GSK3 signaling pathway (see ARF related news story and Baki et al., 2004). Now, work from Edward Koo’s lab at the University of California, San Diego, reveals a wider role for these proteins in the cell signaling pathways that lead to tau phosphorylation, and beyond. The study, published July 13 in the Journal of Biological Chemistry online, shows that PS2, in particular, is necessary for normal expression of the receptor for platelet-derived growth factor (PDGF), and for activation of the neuroprotective Akt and ERK kinase cascades in fibroblasts. But curiously, though PS’s ability to support PDGF receptor expression was abolished by PS FAD mutations, it did not require γ-secretase activity. The results indicate that presenilins are multitaskers whose various functions could contribute to neurodegenerative processes at several levels.
And in another reminder of the importance of Akt activation, a report in last week’s PNAS online, shows that the neuroprotective n-3 fatty acid docosahexaenoic acid (DHA) promotes the speedy membrane translocation and activation of this survival signaling enzyme in neurons from mice fed a diet rich in DHA.
Loss of presenilins and PS FAD mutations lead to neurodegeneration accompanied by suppression of Akt kinase, activation of GSK3, and hyperphosphorylation of tau (see ARF related news story and Baki et al., 2004). In their new study, first author David Kane and colleagues investigated Akt activation in fibroblasts from PS1/2 double knockout mice that had been reconstituted with human PS1 or PS2 alleles. They found that expression of either gene could restore Akt and ERK activation (and decrease tau phosphorylation) in response to whole serum, but only PS2-expressing cells responded to the individual growth factor PDGF. Since PS1 did support some Akt activation in response to serum, the authors hypothesize that there may be other factors that require PS1 for signaling. Their results bring to three the number of receptors whose signaling is affected by presenilins, each by a different mechanism, the others being TrkB and cadherin (Naruse et al., 1998 and Baki et al., 2004).
To answer the question of how PS2 regulates PDGFR signaling, the researchers showed that PS-/- cells lacked PDGFR receptor mRNA and protein. At the same time, the cells displayed a decrease in nuclear localization of FHL2, a transcriptional coactivator that binds to PS2, but not PS1, and is necessary for full PDGF receptor expression. PS2’s ability to reverse these defects did not require γ-secretase activity, but was destroyed by the FAD M239V PS2 mutation. FAD mutations in PS1 were also bad news for PDGFR, as even in cells expressing wild-type PS2, the co-introduction of a FAD PS1 allele interfered with reconstitution and inhibited PDGFR signaling.
The results lead to a picture of how PS loss, or possibly even PS FAD mutations, could contribute to neurodegeneration independently of Aβ production. “Deficits in Akt and ERK activation are predicted to increase the phosphorylation of tau, render neurons more vulnerable to neurodegeneration, and impair learning and memory, precisely as that seen in the PS dKO mice,” the authors write. They speculate that PS mutations could generate a doubly dangerous situation in neurons, where the neurotoxic effects of Akt suppression and tau hyperphosphorylation are exacerbated by enhanced Aβ production to accelerate neurodegeneration.
Activation of the anti-apoptotic Akt pathway by growth factors with the help of presenilins seems to be required to maintain mouse neurons during aging, and probably human ones, as well. If you want to keep that Akt spry, you may want to eat your omega-3 fatty acids. In the PNAS paper, Hee-Yong Kim and colleagues from the NIAAA in Bethesda, Maryland, show that feeding cells, or mice, the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) increases the speed at which Akt moves to the membrane and gets activated in response to the growth factors IGF-1. The ability of DHA to boost phosphatidyl serine content in membranes appeared to account for its positive effects on Akt. The mechanism may explain the beneficial effects of DHA on neurons in an AD mouse model (see ARF related news story and also the comment below from Greg Cole and Sally Frautschy at UCLA), and further supports the study of n-3 fatty acids to protect against AD in humans.—Pat McCaffrey
- The Senility-Presenilin Connection Turned Upside Down
- Fish Oil Swims Ahead in Dietary Brain Protection Race
- Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK. PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J. 2004 Jul 7;23(13):2586-96. PubMed.
- Naruse S, Thinakaran G, Luo JJ, Kusiak JW, Tomita T, Iwatsubo T, Qian X, Ginty DD, Price DL, Borchelt DR, Wong PC, Sisodia SS. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron. 1998 Nov;21(5):1213-21. PubMed.
No Available Further Reading
- Akbar M, Calderon F, Wen Z, Kim HY. Docosahexaenoic acid: a positive modulator of Akt signaling in neuronal survival. Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10858-63. PubMed.
- Kang DE, Yoon IS, Repetto E, Busse T, Yermian N, Ie L, Koo EH. Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem. 2005 Sep 9;280(36):31537-47. PubMed.