A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.
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.
Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Xulun
X
Zhang
Krassimira
K
Garbett
Karthikeyan
K
Veeraraghavalu
Brian
B
Wilburn
Reid
R
Gilmore
Karoly
K
Mirnics
Sangram S
SS
Sisodia
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology; D001755:Blastocyst / Q000378:metabolism; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017931:DNA Primers; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053764:Presenilin-1 / Q000235:genetics / Q000502:physiology*; D053766:Presenilin-2 / Q000235:genetics / Q000502:physiology*; D053763:Presenilins / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D053764:Presenilin-1; D053766:Presenilin-2; D053763:Presenilins; D034741:RNA, Small Interfering; C484068:Tcfeb protein, mouse; D012313:RNA; D002402:Cathepsin D; D025262:Vacuolar Proton-Translocating ATPases