Journal
JOURNAL OF CELL BIOLOGY
Volume 198, Issue 1, Pages 23-35Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201201076
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Funding
- Alzheimer's Association [IIRG-08-91535]
- SAO/FRMA [10010]
- FWO-Vlaanderen [G.0754.10]
- Hercules Foundation [AKUL/09/037]
- Canadian Institutes of Health Research fellowship
- RESTRACOMP fellowship
- CAPES fellowship
- National Institutes of Health [RO1EY018884, RO1GM088803]
- Welch Foundation [I-1657]
- VIB and Katholieke Universiteit Leuven [GOA/11/009]
- Federal Government of Belgium [IAP-P7 2012-17]
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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 sub-units 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.
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