Abstract：
Polymorphisms and altered expression of the Translocase of the Outer Mitochondrial Membrane - 40 kD (Tom40) are observed in neurodegenerative disease subjects. We utilized in vitro cultured dorsal root ganglion (DRG) neurons to investigate the association of TOM40 depletion to neurodegeneration, and to unravel the mechanism of neurodegeneration induced by decreased levels of TOM40 protein. We provide evidence that severity of neurodegeneration induced in the TOM40 depleted neurons increases with the increase in the depletion of TOM40 and is exacerbated by an increase in the duration of TOM40 depletion. We also demonstrate that TOM40 depletion causes a surge in neuronal calcium levels, decreases mitochondrial motility, increases mitochondrial fission, and decreases neuronal ATP levels. We observed that alterations in the neuronal calcium homeostasis and mitochondrial dynamics precede BCL-xl and NMNAT1 dependent neurodegenerative pathways in the TOM40 depleted neurons. This data also suggests that manipulation of BCL-xl and NMNAT1 may be of therapeutic value in TOM40 associated neurodegenerative disorders.
摘要：
在神经退行性疾病受试者中观察到线粒体外膜转位酶-40kD(Tom40)的多态性和表达改变。我们利用体外培养的背根神经节（DRG）神经元来研究TOM40耗竭与神经变性的关系，并阐明TOM40蛋白水平降低导致神经变性的机制。我们提供证据表明，在TOM40耗竭神经元中诱导的神经变性的严重程度随着TOM40耗竭的增加而增加，并且由于TOM40耗竭持续时间的增加而加剧。我们还证明，TOM40耗竭导致神经元钙水平激增，降低线粒体运动性，增加线粒体裂变，并降低神经元ATP水平。我们观察到，在TOM40耗竭的神经元中，神经元钙稳态和线粒体动力学的改变先于BCL-xl和NMNAT1依赖性神经退行性通路。该数据还表明BCL-xl和NMNATl的操作在TOM40相关的神经退行性疾病中可能具有治疗价值。
