Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells

Katrijn Coen, Ronald S. Flannagan, Szilvia Baron, Luciene R. Carraro-Lacroix, Dong Wang, Wendy Vermeire, Christine Michiels, Sebastian Munck, Veerle Baert, Shuzo Sugita, Frank Wuytack, Peter Robin Hiesinger, Sergio Grinstein, Wim Annaert

Research output: Contribution to journalArticle

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)23-35
Number of pages13
JournalJournal of Cell Biology
Volume198
Issue number1
DOIs
StatePublished - Jul 9 2012

ASJC Scopus subject areas

  • Cell Biology

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    Coen, K., Flannagan, R. S., Baron, S., Carraro-Lacroix, L. R., Wang, D., Vermeire, W., Michiels, C., Munck, S., Baert, V., Sugita, S., Wuytack, F., Hiesinger, P. R., Grinstein, S., & Annaert, W. (2012). Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. Journal of Cell Biology, 198(1), 23-35. https://doi.org/10.1083/jcb.201201076