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Hum Mol Genet. 2014 Dec 15;23(24):6567-74. doi: 10.1093/hmg/ddu377. Epub 2014 Jul 22.

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

Author information

1
Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing 100875, China, Transgenics Section and and.
2
Transgenics Section and and.
3
Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
4
Transgenics Section and and caih@mail.nih.gov.

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.

PMID:
25051958
PMCID:
PMC4240205
DOI:
10.1093/hmg/ddu377
[Indexed for MEDLINE]
Free PMC Article

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