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Featured ArticleArticles, Cellular/Molecular

A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2

Xulun Zhang, Krassimira Garbett, Karthikeyan Veeraraghavalu, Brian Wilburn, Reid Gilmore, Karoly Mirnics and Sangram S. Sisodia
Journal of Neuroscience 20 June 2012, 32 (25) 8633-8648; DOI: https://doi.org/10.1523/JNEUROSCI.0556-12.2012
Xulun Zhang
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Krassimira Garbett
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Karthikeyan Veeraraghavalu
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Brian Wilburn
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Reid Gilmore
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Karoly Mirnics
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Sangram S. Sisodia
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Abstract

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.

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The Journal of Neuroscience: 32 (25)
Journal of Neuroscience
Vol. 32, Issue 25
20 Jun 2012
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A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2
Xulun Zhang, Krassimira Garbett, Karthikeyan Veeraraghavalu, Brian Wilburn, Reid Gilmore, Karoly Mirnics, Sangram S. Sisodia
Journal of Neuroscience 20 June 2012, 32 (25) 8633-8648; DOI: 10.1523/JNEUROSCI.0556-12.2012

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A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2
Xulun Zhang, Krassimira Garbett, Karthikeyan Veeraraghavalu, Brian Wilburn, Reid Gilmore, Karoly Mirnics, Sangram S. Sisodia
Journal of Neuroscience 20 June 2012, 32 (25) 8633-8648; DOI: 10.1523/JNEUROSCI.0556-12.2012
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  • Presenilins and Lysosome pH Revisited Again
    Ralph Nixon
    Published on: 05 December 2012
  • Published on: (5 December 2012)
    Page navigation anchor for Presenilins and Lysosome pH Revisited Again
    Presenilins and Lysosome pH Revisited Again
    • Ralph Nixon, Professor, Director
    • Other Contributors:
      • Ju-hyun Lee, Devin Wolfe

    Zhang et al. report that autophagy is normal in presenilin 1 (PS1) KO or presenilin 1/ 2 (PS1/2) DKO cells, a conclusion differing from findings in five laboratories that have demonstrated autophagy pathology and accumulation of autophagy substrates consistent with impaired autophagy in PS1-deficient cells (Esselens et al., 2004; Wilson et al., 2004; Lee et al., 2010; Neely et al., 2011; Dobrowolski et al., 2012). The "ves...

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    Zhang et al. report that autophagy is normal in presenilin 1 (PS1) KO or presenilin 1/ 2 (PS1/2) DKO cells, a conclusion differing from findings in five laboratories that have demonstrated autophagy pathology and accumulation of autophagy substrates consistent with impaired autophagy in PS1-deficient cells (Esselens et al., 2004; Wilson et al., 2004; Lee et al., 2010; Neely et al., 2011; Dobrowolski et al., 2012). The "vesicle" pH of ~ 6.6 they report for WT and PS1KO cells has questionable relevance to lysosomal pH, which is widely accepted to be ~ 5.0. Unlike the lysosome-targeted pH probe we used, the unconjugated Lysosensor DND-160 probe used in the Zhang et al. study labeled undefined intracellular compartments that the authors acknowledged in the Results were not specifically lysosomes, despite their paper's title. This may partly explain the surprising finding in their Figure 2 that more than 85% of the pH values measured in wild-type cells were higher than pH 7.0. Of additional concern, the authors eliminated, for unexplained reasons, >75% of their readings, which exceeded the upper limit of their standard curve (pH 8.0) in calculating the "vesicle" pH of wild-type cells. They also eliminated different percentages of the pH values measured in each of the PS1-deficient cell lines that were compared with wild-type cells.

    Using an siRNA approach, Zhang et al. also report that, "We failed to detect any effects on the maturation of V0a1-6His by reducing the levels of either STT3A or STT3B." However, later in Results and consistent with our findings, they conclude the opposite, stating "... taken together our results indicate that the glycosylation site in V0a1 can be glycosylated by both the STT3A and STT3B isoforms of the OST." In this experiment, pro-Cathepsin C glycosylation, used as a positive control to establish the effectiveness of STT3B siRNA, remained unchanged after STT3B siRNA treatment, which would make any negative finding on V0a1 glycosylation after STT3B knockdown difficult to interpret.

    References

    Dobrowolski R, Vick P, Ploper D, Gumper I, Snitkin H, Sabatini DD, De Robertis EM (2012) Presenilin Deficiency or Lysosomal Inhibition Enhances Wnt Signaling through Relocalization of GSK3 to the Late-Endosomal Compartment. Cell Rep 2:1316-28.

    Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, Zheng H, Saftig P, De Strooper B, Klumperman J, Annaert W (2004) Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol 166:1041-1054.

    Lee J-H, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA (2010) Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations. Cell 141:1146-1158.

    Neely KM, Green KN, LaFerla FM (2011) Presenilin Is Necessary for Efficient Proteolysis through the Autophagy-Lysosome System in a g- Secretase-Independent Manner. J Neurosci 31:2781-2791.

    Wilson CA, Murphy DD, Giasson BI, Zhang B, Trojanowski JQ, Lee VM (2004) Degradative organelles containing mislocalized a- and b-synuclein proliferate in presenilin-1 null neurons. J Cell Biol 165:335-346.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.

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