title: Dissociation of progressive dopaminergic neuronal death and behavioral impairments by Bax deletion in a mouse model of Parkinson's diseases.
abstract: Parkinson's disease (PD) is a common, late-onset movement disorder with selective degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Although the neurotoxin 6-hydroxydopamine (6-OHDA) has been used to induce progressive degeneration of DA neurons in various animal models of PD, the precise molecular pathway and the impact of anti-apoptotic treatment on this neurodegeneration are less understood. Following a striatal injection of 6-OHDA, we observed atrophy and progressive death of DA neurons in wild-type mice. These degenerating DA neurons never exhibited signs of apoptosis (i.e., caspase-3 activation and cytoplasmic release of cytochrome C), but rather show nuclear translocation of apoptosis-inducing factor (AIF), a hallmark of regulated necrosis. However, mice with genetic deletion of the proapoptotic gene Bax (Bax-KO) exhibited a complete absence of 6-OHDA-induced DA neuron death and nuclear translocation of AIF, indicating that 6-OHDA-induced DA neuronal death is mediated by Bax-dependent AIF activation. On the other hand, DA neurons that survived in Bax-KO mice exhibited marked neuronal atrophy, without significant improvement of PD-related behavioral deficits. These findings suggest that anti-apoptotic therapy may not be sufficient for PD treatment, and the prevention of Bax-independent neuronal atrophy may be an important therapeutic target.
authors: BK21 Program, Department of Anatomy, Korea University College of Medicine, Sungbuk-Gu, Seoul, Korea.
authors: Tae Woo
authors: TW
authors: Kim
authors: Younghye
authors: Y
authors: Moon
authors: Kyungjin
authors: K
authors: Kim
authors: Jeong Eun
authors: JE
authors: Lee
authors: Hyun Chul
authors: HC
authors: Koh
authors: Im Joo
authors: IJ
authors: Rhyu
authors: Hyun
authors: H
authors: Kim
authors: Woong
authors: W
authors: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001284:Atrophy; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D001523:Mental Disorders / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D013378:Substantia Nigra / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000172:deficiency* / Q000235:genetics
chemical_list: D051033:Apoptosis Inducing Factor; C494827:Bax protein, mouse; D051028:bcl-2-Associated X Protein; D016627:Oxidopamine