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

110 Citations (Scopus)

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

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Presenilins
Proton Pumps
Vacuolar Proton-Translocating ATPases
Homeostasis
Glycosylation
Calcium
Lysosomes
Endosomes
Drosophila melanogaster
Endoplasmic Reticulum
Neurons

ASJC Scopus subject areas

  • Cell Biology

Cite this

Coen, K., Flannagan, R. S., Baron, S., Carraro-Lacroix, L. R., Wang, D., Vermeire, W., ... 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

Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. / Coen, Katrijn; Flannagan, Ronald S.; Baron, Szilvia; Carraro-Lacroix, Luciene R.; Wang, Dong; Vermeire, Wendy; Michiels, Christine; Munck, Sebastian; Baert, Veerle; Sugita, Shuzo; Wuytack, Frank; Hiesinger, Peter Robin; Grinstein, Sergio; Annaert, Wim.

In: Journal of Cell Biology, Vol. 198, No. 1, 09.07.2012, p. 23-35.

Research output: Contribution to journalArticle

Coen, K, Flannagan, RS, Baron, S, Carraro-Lacroix, LR, Wang, D, Vermeire, W, Michiels, C, Munck, S, Baert, V, Sugita, S, Wuytack, F, Hiesinger, PR, 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, vol. 198, no. 1, pp. 23-35. https://doi.org/10.1083/jcb.201201076
Coen, Katrijn ; Flannagan, Ronald S. ; Baron, Szilvia ; Carraro-Lacroix, Luciene R. ; Wang, Dong ; Vermeire, Wendy ; Michiels, Christine ; Munck, Sebastian ; Baert, Veerle ; Sugita, Shuzo ; Wuytack, Frank ; Hiesinger, Peter Robin ; Grinstein, Sergio ; Annaert, Wim. / Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. In: Journal of Cell Biology. 2012 ; Vol. 198, No. 1. pp. 23-35.
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