Activation of ataxia telangiectasia muted under experimental models and human 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.
Camins
Antoni
A
Institut de Biomedicina, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universitat de Barcelona, Spain. camins@ub.edu
Pizarro
Javier G
JG
Alvira
Daniel
D
Gutierrez-Cuesta
Javier
J
de la Torre
Aurelio Vazquez
AV
Folch
Jaume
J
Sureda
Francesc X
FX
Verdaguer
Ester
E
Junyent
Felix
F
Jordán
Joaquín
J
Ferrer
Isidre
I
Pallàs
Mercè
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009025:Morpholines; D009498:Neurotoxins; D011753:Pyrones; D025521:Tumor Suppressor Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases