دورية أكاديمية
Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification
| العنوان: | Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification |
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| المؤلفون: | Ju-Hyun Lee, Mary Kate McBrayer, Devin M. Wolfe, Luke J. Haslett, Asok Kumar, Yutaka Sato, Pearl P.Y. Lie, Panaiyur Mohan, Erin E. Coffey, Uday Kompella, Claire H. Mitchell, Emyr Lloyd-Evans, Ralph A. Nixon |
| المصدر: | Cell Reports, Vol 12, Iss 9, Pp 1430-1444 (2015) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2015 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Biology (General), QH301-705.5 |
| الوصف: | Presenilin 1 (PS1) deletion or Alzheimer’s disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO) cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2211-1247 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2211124715008281Test; https://doaj.org/toc/2211-1247Test; https://doaj.org/article/4b67173bf3dc4cc4a3ad2615020ddeb6Test |
| DOI: | 10.1016/j.celrep.2015.07.050 |
| الإتاحة: | https://doi.org/10.1016/j.celrep.2015.07.050Test https://doaj.org/article/4b67173bf3dc4cc4a3ad2615020ddeb6Test |
| رقم الانضمام: | edsbas.E83A4ED8 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 22111247 |
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| DOI: | 10.1016/j.celrep.2015.07.050 |