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(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease
Authors:T W Kim  H M Cho  S Y Choi  Y Suguira  T Hayasaka  M Setou  H C Koh  E Mi Hwang  J Y Park  S J Kang  H S Kim  H Kim  W Sun
Abstract:Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson''s disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.
Keywords:PARP-1  ATP  AMPK  6-OHDA  Parkinson''s disease
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