, 2008) Additionally, lateral ventricular injection of sAPPα inc

, 2008). Additionally, lateral ventricular injection of sAPPα increased the proliferation of NPCs in the subventricular zone, another neurogenic niche

in mouse brain ( Caillé et al., 2004). All ADAM family proteins contain an N-terminal prodomain, which acts to chaperone and ensure the proper Metabolism inhibitor folding of this family of metalloproteases. Our results show that the cleaved ADAM10 prodomain appears to be quickly degraded in the brain and that cellular trafficking of ADAM10 is not affected by the prodomain mutations. Interestingly, while the prodomain may be degraded, it may still have the ability to affect the mature enzyme via its intramolecular chaperone function. This phenomenon, dubbed “protein memory,” was reported in mutant subtilysin, a serine protease harboring a mutation in its prodomain (Shinde et al., 1997). The point mutation yielded mature subtilysin that had a different structure and activity via “structural imprinting” during protein folding (Shinde et al., Selleckchem CT99021 1997). Improperly chaperoned, mis-folded proteases can be restructured and become active

by ectopic expression of WT prodomain (Cao et al., 2000). In our mammalian cell-based studies, WT but not mutant ADAM10 prodomain rescued the α-secretase activity of inactive ADAM10 expressed from a prodomain-deleted cDNA construct. This indicates impairment of the chaperone function of the prodomain by the LOAD mutations (Figure 8C). In further support of this conclusion, secondary structure predictions showed that the only α-helix in the prodomain can be terminated by the R181G mutation (McGuffin

et al., 2000). To date, a few pathogenic amino acid substitutions, which are Farnesyltransferase not present in the mature forms, have been associated with diseases. But to our knowledge, the two LOAD ADAM10 mutations are the first to be associated with the etiology of any disease by impairing the intramolecular chaperone function of a prodomain. Increased ADAM10 α-secretase activity could potentially be achieved by multiple different mechanisms, including the activation of ADAM10 gene transcription by retinoic acid, the inhibition of natural ADAM10 inhibitors (e.g., TIMPs, tissue inhibitor of metalloproteases), and the modulation of ADAM10 cellular trafficking (Lichtenthaler, 2011). While dozens of proteins have been reported as ADAM10 substrates (Pruessmeyer and Ludwig, 2009), only a handful are related to brain and neuronal function. Moreover, in contrast to the ADAM10 knockdown, our data and a previous report by Postina et al. (2004) support that modest elevation of ADAM10 is relatively well tolerated and does not affect Notch1 signaling in adult brain.

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