Here, PSEN proteins contain two key aspartic acid residues necessary for the proteolytic activity of the complex in cleaving a range of substrates including the amyloid-β and NOTCH proteins. The role of the γ-secretase complex is primarily thought to be through its proteolytic activity and cleavage of target proteins. These studies have given rise to a theory of neurodegenerative disease pathology relating to reduced protein clearance. Dysfunctional endosomal-lysosomal and autophagic pathways have also been implicated in the pathogenesis of several other neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Parkinson disease. This role has been implicated in disease pathology, since mutations in PSEN1 proteins associated with familial Alzheimer disease result in elevated lysosomal pH, and aberrant autophagy in mouse models. One function of the mammalian complex (consisting of PSEN1, APH1, NCSTN and PSENEN/PEN2 ) or PSEN1 proteins alone is to regulate endocytosis, lysosomal acidification, and autophagy. Many studies have sought to explore a role for the γ-secretase complex (and PSEN proteins) in the pathology of Alzheimer disease. Our data therefore demonstrates an evolutionarily conserved non-proteolytic role for presenilin, and γ-secretase component orthologs, in maintaining Dictyostelium lysosomal trafficking and autophagy. Importantly, we find that all the endocytic defects observed in Dictyostelium PSEN ortholog mutants can be fully rescued by proteolytically inactive Dictyostelium psenB and human PSEN1 proteins. This indicates a general defect in lysosomal trafficking and degradation, which we show leads to the accumulation of ubiquitinated protein aggregates in cells lacking psenA/B and Aph-1 proteins. Disruption of either psenA/B or Aph-1 proteins also leads to disrupted phagosomal proteolysis as well as decreased autophagosomal acidification and autophagic flux. In this model, we show that the orthologs of PSEN (psenA and psenB), Ncstn (nicastrin) and Aph-1 (gamma-secretase subunit Aph-1), are necessary for optimal fluid-phase uptake by macropinocytosis and in multicellular development under basic pH conditions.
Here, we dissect the roles of orthologs of the γ-secretase components in the model system Dictyostelium, focusing on endocytosis, lysosomal activity and autophagy. Both proteolytic and non-proteolytic functions for the γ-secretase complex have been previously described in mammalian model organisms, but their relative contributions to disease pathology remain unclear. Mutations in the γ-secretase complex are strongly associated with familial Alzheimer disease.
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