title: A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons.
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.
authors: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing 100875, China, Transgenics Section and and.
authors: Jing
authors: J
authors: Luo
authors: Transgenics Section and and.
authors: Lixin
authors: L
authors: Sun
authors: Transgenics Section and and.
authors: Xian
authors: X
authors: Lin
authors: Transgenics Section and and.
authors: Guoxiang
authors: G
authors: Liu
authors: Transgenics Section and and.
authors: Jia
authors: J
authors: Yu
authors: Transgenics Section and and.
authors: Loukia
authors: L
authors: Parisiadou
authors: Transgenics Section and and.
authors: Chengsong
authors: C
authors: Xie
authors: Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Jinhui
authors: J
authors: Ding
authors: Transgenics Section and and caih@mail.nih.gov.
authors: Huaibin
authors: H
authors: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D051844:alpha-Synuclein; D016572:Cyclosporine; D019703:Calcineurin