Abstract
Gamma–secretase catalyzes the cleavage of a variety of different type 1 transmembrane proteins. We recently showed that the sorting receptors Sortilin, SorLA and SorCS1 are gamma–secretase substrates. These receptors have pleiotropic functions in chaperoning and targeting various cargoes bound to their luminal domains between various intracellular organelles. There is some evidence that members of this family may have functional consequences in AD. ProNGF death signaling occurs when proNGF is in a complex with two gamma–secretase substrates (Sortilin and p75NTR). Additionally, SorLA has been shown to be decreased in AD brain and modulates Abeta production. We are exploring the potential roles that these sorting receptors may play in AD. ProNGF has been shown to increase with age and is markedly increased in mild cognitive impairment and AD patients. We aim to determine if gamma–secretase cleavage of either Sortilin or p75NTR play a role in proNGF mediated neuronal loss. Using cell culture systems we have determined that Sortilin, SorLA and SorCS1 are gamma–secretase substrates. Experiments are currently underway to determine if gamma–secretae cleavage of these sorting receptors modulates an AD like phenotype. Preliminary results using Adeno–Associated Viral gene delivery to express a non–maturing proNGF construct in mice suggest that proNGF causes significant neuronal loss. Our results suggest that these sorting receptors are cleaved by gamma–secretase and that they may play a role in AD progression.
Published Version
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