Buffering of cytosolic calcium plays a neuroprotective role by preserving the autophagy-lysosome pathway during MPP+-induced neuronal death

Shinae Jung, Yuhyun Chung, Yunsoo Lee, Yangsin Lee, Jin Won Cho, Eun Joo Shin, Hyoung Chun Kim, Young J. Oh

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13 Citations (Scopus)


Parkinson’s disease (PD) is a chronic neurodegenerative disease with no cure. Calbindin, a Ca2+-buffering protein, has been suggested to have a neuroprotective effect in the brain tissues of PD patients and in experimental models of PD. However, the underlying mechanisms remain elusive. Here, we report that in 1-methyl-4-phenylpyridinium (MPP+)-induced culture models of PD, the buffering of cytosolic Ca2+ by calbindin-D28 overexpression or treatment with a chemical Ca2+ chelator reversed impaired autophagic flux, protecting cells against MPP+-mediated neurotoxicity. When cytosolic Ca2+ overload caused by MPP+ was ameliorated, the MPP+-induced accumulation of autophagosomes decreased and the autophagic flux significantly increased. In addition, the accumulation of damaged mitochondria and p62-positive ubiquitinated protein aggregates, following MPP+ intoxication, was alleviated by cytosolic Ca2+ buffering. We showed that MPP+ treatment suppressed autophagic degradation via raising the lysosomal pH and therefore reducing cytosolic Ca2+ elevation restored the lysosomal pH acidity and normal autophagic flux. These results support the notion that functional lysosomes are required for Ca2+-mediated cell protection against MPP+-mediated neurotoxicity. Thus, our data suggest a novel process in which the modulation of Ca2+ confers neuroprotection via the autophagy-lysosome pathway. This may have implications for the pathogenesis and future therapeutic targets of PD.

Original languageEnglish
Article number130
JournalCell Death Discovery
Issue number1
Publication statusPublished - 2019 Dec 1

Bibliographical note

Funding Information:
This work was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Korean Government (2017M37A1025369 to Y.J.O.), and partly by NRF-2016R1A5A1010764 (to J.W.C.).

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


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