Umeå University's logo

umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The coordinated action of calcineurin and cathepsin d protects against α-synuclein toxicity
Institute of Molecular Biosciences, University of Graz, Graz, Austria.ORCID iD: 0000-0002-1241-162X
Show others and affiliations
2017 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 207Article in journal (Refereed) Published
Abstract [en]

The degeneration of dopaminergic neurons during Parkinson’s disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human αSyn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased αSyn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces αSyn cytotoxicity.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2017. Vol. 10, article id 207
Keywords [en]
Calcineurin, Cathepsin D, Cytosolic acidification, Parkinson’s disease, Pep4, PH homeostasis, Vacuole, α-synuclein
National Category
Cell Biology Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-215042DOI: 10.3389/fnmol.2017.00207ISI: 000404446800002PubMedID: 28713240Scopus ID: 2-s2.0-85026645397OAI: oai:DiVA.org:umu-215042DiVA, id: diva2:1802945
Funder
Swedish Research Council, 2015-05468Carl Tryggers foundation , CTS16:85Stiftelsen Sigurd och Elsa Goljes minne, LA2016-0123Åke Wiberg Foundation, M16-0130Available from: 2023-10-06 Created: 2023-10-06 Last updated: 2023-10-16Bibliographically approved

Open Access in DiVA

fulltext(4952 kB)14 downloads
File information
File name FULLTEXT01.pdfFile size 4952 kBChecksum SHA-512
fe70365e3834fa250997fd4998fc328ce5e9d1d09d9c1828adcbd560e21c30e21516606f23ae6ae075533aac1dc075fd5e6caab1ee8b4f351050091ecf5beb2e
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMedScopus

Authority records

Kohler, AndreasKohler, Verena

Search in DiVA

By author/editor
Kohler, AndreasKohler, Verena
In the same journal
Frontiers in Molecular Neuroscience
Cell BiologyNeurosciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 14 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 103 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf