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Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function.

ABSTRACT: Mutations in the ?-secretase complex are strongly associated with familial Alzheimer disease. Both proteolytic and non-proteolytic functions for the ?-secretase complex have been previously described in mammalian model organisms, but their relative contributions to disease pathology remain unclear. Here, we dissect the roles of orthologs of the ?-secretase components in the model system Dictyostelium, focusing on endocytosis, lysosomal activity and autophagy. 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. Disruption of either psenA/B or Aph-1 proteins also leads to disrupted phagosomal proteolysis as well as decreased autophagosomal acidification and autophagic flux. 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. 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. Our data therefore demonstrates an evolutionarily conserved non-proteolytic role for presenilin, and ?-secretase component orthologs, in maintaining Dictyostelium lysosomal trafficking and autophagy. Abbreviations: Atg8: autophagy protein 8a; Aph-1: gamma-secretase subunit Aph-1; crtA: calreticulin; ER: endoplasmic reticulum; GFP: green fluorescent protein; GSK3B: glycogen synthase kinase 3 beta; Ncstn: nicastrin; PSEN1: presenilin 1; psenA and psenB: Dictyostelium presenilin A and B; TRITC; tetramethylrhodamine isothiocyanate.

SUBMITTER: Sharma D

PROVIDER: S-EPMC6613883 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in <i>Dictyostelium discoideum</i>, independent of PSEN (presenilin) proteolytic function.

Sharma Devdutt D Otto Grant G Warren Eleanor C EC Beesley Philip P King Jason S JS Williams Robin S B RSB

Autophagy 20190321 8

Mutations in the γ-secretase complex are strongly associated with familial Alzheimer disease. 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. Here, we dissect the roles of orthologs of the γ-secretase components in the model system <i>Dictyostelium</i>, focusing on endocytosis, lysosomal activity and autophagy. In this model, we show that t ...[more]

PMID: 30806144

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Project description:Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS-/- cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD.

Dataset Information

Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function.

Publications

Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in <i>Dictyostelium discoideum</i>, independent of PSEN (presenilin) proteolytic function.

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