Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease

作者：Camins Antoni^*; Pizarro Javier G; Alvira Daniel; Gutierrez Cuesta Javier; de la Torre Aurelio Vazquez; Folch Jaume; Sureda Francesc X; Verdaguer Ester; Junyent Felix; Jordan Joaquin; Ferrer Isidre; Pallas Merce

来源：Cellular and Molecular Life Sciences, 2010, 67(22): 3865-3882.

DOI：10.1007/s00018-010-0408-5

• ATM
• MPP(+)
• Cell cycle
• Apoptosis
• Retinoblastoma protein
• B65 neuroblastoma
• Parkinson's disease

In the present study we demonstrated that neurotoxin MPP(+)-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP(+)-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson's disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G(0)/G(1) cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP(+) leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP(+) and cell-cycle re-entry through retinoblastoma protein phosphorylation.

• 出版日期2010-11