title: Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells.
abstract: Presenilin (PSEN) deficiency is accompanied by accumulation of endosomes and autophagosomes, likely caused by impaired endo-lysosomal fusion. Recently, Lee et al. (2010. Cell. doi: http://dx.doi.org/10.1016/j.cell.2010.05.008) attributed this phenomenon to PSEN1 enabling the transport of mature V0a1 subunits of the vacuolar ATPase (V-ATPase) to lysosomes. In their view, PSEN1 mediates the N-glycosylation of V0a1 in the endoplasmic reticulum (ER); consequently, PSEN deficiency prevents V0a1 glycosylation, compromising the delivery of unglycosylated V0a1 to lysosomes, ultimately impairing V-ATPase function and lysosomal acidification. We show here that N-glycosylation is not a prerequisite for proper targeting and function of this V-ATPase subunit both in vitro and in vivo in Drosophila melanogaster. We conclude that endo-lysosomal dysfunction in PSEN(-/-) cells is not a consequence of failed N-glycosylation of V0a1, or compromised lysosomal acidification. Instead, lysosomal calcium storage/release is significantly altered in PSEN(-/-) cells and neurons, thus providing an alternative hypothesis that accounts for the impaired lysosomal fusion capacity and accumulation of endomembranes that accompanies PSEN deficiency.
authors: Department of Human Genetics, VIB Center for the Biology of Disease, Leuven, Belgium.
authors: Katrijn
authors: K
authors: Coen
authors: Ronald S
authors: RS
authors: Flannagan
authors: Szilvia
authors: S
authors: Baron
authors: Luciene R
authors: LR
authors: Carraro-Lacroix
authors: Dong
authors: D
authors: Wang
authors: Wendy
authors: W
authors: Vermeire
authors: Christine
authors: C
authors: Michiels
authors: Sebastian
authors: S
authors: Munck
authors: Veerle
authors: V
authors: Baert
authors: Shuzo
authors: S
authors: Sugita
authors: Frank
authors: F
authors: Wuytack
authors: Peter Robin
authors: PR
authors: Hiesinger
authors: Sergio
authors: S
authors: Grinstein
authors: Wim
authors: W
authors: Annaert
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D025262:Vacuolar Proton-Translocating ATPases; C550849:Vha100-1 protein, Drosophila; D002118:Calcium