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Cited by 79Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingSignaling Pathways in Disease

A calcineurin- and NFAT-dependent pathway is involved in -synuclein-induced degeneration of midbrain dopaminergic neurons

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Luo, J., Sun, L., Lin, X., Liu, G., Yu, J., Parisiadou, L., Xie, C., Ding, J. +1 more·2014·Human Molecular Genetics
DOI 10.1093/hmg/ddu377PMC PMC4240205
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Abstract

Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD.

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Cited by

Sorted by citations

Authors
Luo, J., Sun, L., Lin, X., Liu, G., Yu, J., Parisiadou, L., Xie, C., Ding, J., & Cai, H.
Affiliations
  • Beijing Normal University (CN)
  • National Institutes of Health (US)
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2014-07-22
Volume
23
Issue
24
Pages
6567-6574
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddu377
PMC
PMC4240205
OpenAlex
W2106072892
Cited by
79
References
3
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 17 · 2022: 11 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 10 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 1
FWCI
3.48
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China
  • Sun Yat-sen University
  • National Institute on Aging (AG-000929, AG-000928, ZIAAG000928, ZIAAG000929)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Parkinson's disease, alpha-synuclein, midbrain dopaminergic neurons, neurodegeneration, calcineurin, NFATc3, cyclosporine, neuroprotection, transgenic mice
MeSH terms
Animals, Gene Expression Regulation, Humans, Mesencephalon, Mice, Transgenic, Mutation, Parkinson Disease, Signal Transduction, Cyclosporine, Apoptosis, Calcineurin, NFATC Transcription Factors, Mice, alpha-Synuclein, HEK293 Cells, Dopaminergic Neurons, Primary Cell Culture, Calcineurin Inhibitors

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