A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.

Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K, Sisodia SS
J Neurosci. 2012 32 (25): 8633-48

PMID: 22723704 · PMCID: PMC3467018 · DOI:10.1523/JNEUROSCI.0556-12.2012

Presenilins 1 and 2 (PS1 and PS2) are the catalytic subunits of the γ-secretase complex, and genes encoding mutant PS1 and PS2 variants cause familial forms of Alzheimer's disease. Lee et al. (2010) recently reported that loss of PS1 activity lead to impairments in autophagosomal function as a consequence of lysosomal alkalinization, caused by failed maturation of the proton translocating V0a1 subunit of the vacuolar (H+)-ATPase and targeting to the lysosome. We have reexamined these issues in mammalian cells and in brains of mice lacking PS (PScdko) and have been unable to find evidence that the turnover of autophagic substrates, vesicle pH, V0a1 maturation, or lysosome function is altered compared with wild-type counterparts. Collectively, our studies fail to document a role for presenilins in regulating cellular autophagosomal function. On the other hand, our transcriptome studies of PScdko mouse brains reveal, for the first time, a role for PS in regulating lysosomal biogenesis.

MeSH Terms (23)

Animals Autophagy Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Blastocyst Blotting, Western Cathepsin D Cell Line, Tumor Cells, Cultured DNA Primers Gene Expression Humans Hydrogen-Ion Concentration Lysosomes Mice Mice, Knockout Neurons Polymerase Chain Reaction Presenilin-1 Presenilin-2 Presenilins RNA RNA, Small Interfering Vacuolar Proton-Translocating ATPases

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