| First Author | Luo J | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 24 | Pages | 6567-74 |
| PubMed ID | 25051958 | Mgi Jnum | J:216227 |
| Mgi Id | MGI:5608534 | Doi | 10.1093/hmg/ddu377 |
| Citation | Luo J, et al. (2014) A calcineurin- and NFAT-dependent pathway is involved in alpha-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum Mol Genet 23(24):6567-74 |
| abstractText | Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both alpha-synuclein (alpha-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of alpha-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human alpha-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. alpha-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T alpha-syn. Furthermore, overexpression of alpha-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 alpha-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in alpha-syn-mediated degeneration of mDA neurons in PD. |
