(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease.
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.
Department of Anatomy, BK21 program, Korea University College of Medicine, 126-1 Anam-Dong, Sungbuk-Gu, Seoul 136-705, Korea.
T W
TW
Kim
H M
HM
Cho
S Y
SY
Choi
Y
Y
Suguira
T
T
Hayasaka
M
M
Setou
H C
HC
Koh
E Mi
EM
Hwang
J Y
JY
Park
S J
SJ
Kang
H S
HS
Kim
H
H
Kim
W
W
Sun
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism
D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; D004298:Dopamine