24 October 2004. Venturing off the beaten path, Bryce Carey yesterday presented a poster at the 34th annual conference of the Society for Neuroscience about the interaction between an MCH class 1 protein and γ-secretase. The list of substrates for this key enzyme in amyloid production is growing continuously, but most of these substrates do not currently receive intense scrutiny for a possible role in the development of Alzheimer’s. This could change, however, if the notion becomes more firmly established that γ-secretase acts in AD pathogenesis not by a straightforward gain of function (i.e., Aβ production), but by a more subtle mix of partial gain and partial loss of function. Inklings of this trend pervade the field, and if it became more widely recognized, scientists will study the long list of γ-secretase targets with renewed interest to understand the broader role this proteolytic complex could have in AD and aging.
What’s with HLA, then? Carey, a technician in Dora Kovacs’s lab at Massachusetts General Hospital in Charlestown, began pursuing it when a sequence comparison showed that HLA-2A has an intramembrane domain shared by γ-secretase targets. But wait, you say—HLA is not a neuronal protein. True, it’s one of two classes of antigen-presenting membrane proteins, and its many varieties are traditionally thought to be expressed only on immune cells, where they present antigen to T cells to crank up an immune response. But a few years ago, Carla Shatz’s group at Harvard Medical School discovered to their surprise that developing, and indeed adult, mouse neurons express it, as well, and that lab is now studying class 1 MCH proteins for a possible function in the activity-dependent pruning that shapes the neonatal nervous system (see ARF related news story and ARF news).
In yesterday’s poster, Carey identifies the HLA-A2 as a substrate of α- and γ-secretase-mediated cleavage. He expressed HLA-A2 in CHO cells, and found that it undergoes ectodomain shedding when he also expressed ADAM-10, the leading candidate for the α-secretase role (see (see ARF related news story on Postina et al., 2004). This cleavage gives rise to a soluble piece and a membrane-anchored piece. The latter one then gets clipped further by γ-secretase, yielding a final soluble snippet that the cells quickly degrade, Carey’s poster suggests. Further experiments indicate that HLA-A2 forms a complex with β2-microglobulin, as indeed it normally does in lymphocytes. When Carey inhibited γ-secretase, less HLA was presented at the surface, hinting that γ-secretase cleavage might have to do with getting it there or be recycled properly.
If confirmed, one implication of this early work is that it could help explain why some γ-secretase inhibitor drugs interfere with T cell maturation (see ARF related news story). Furthermore, it might illuminate why some presenilin double knockout strains show changes in their thymocyte populations and mild autoimmune symptoms (see Tournoy et al., 2004). But most intriguing, perhaps, is speculation about what it might be doing in adult brain.—Gabrielle Strobel.