dissociation of progressive dopaminergic neuronal death and behavioral impairments by bax deletion in a mouse model of parkinsons diseases离解的进步的多巴胺能神经元死亡和伯灵顿删除行为障碍的帕金森疾病的小鼠模型.pdfVIP

Dissociation of Progressive Dopaminergic Neuronal Death and Behavioral Impairments by Bax Deletion in a Mouse Model of Parkinson’s Diseases 1 1,2 2 3 3 1 Tae Woo Kim , Younghye Moon , Kyungjin Kim , Jeong Eun Lee , Hyun Chul Koh , Im Joo Rhyu , Hyun 1 1 Kim , Woong Sun * 1 BK21 Program, Department of Anatomy, Korea University College of Medicine, Sungbuk-Gu, Seoul, Korea, 2 Department of Biological Sciences, Seoul National University, Seoul, Korea, 3 Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Korea 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,