Inserm U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, F-67085, France.
Pharmacol Ther. 2011 Jun;130(3):348-63. doi: 10.1016/j.pharmthera.2011.03.004. Epub 2011 Mar 21.
Cytoplasmic dynein 1 (later referred to as dynein) is the major molecular motor moving cargoes such as mitochondria, organelles and proteins towards the minus end of microtubules. Dynein is involved in multiple basic cellular functions, such as mitosis, autophagy and structure of endoplasmic reticulum and Golgi, but also in neuron specific functions in particular retrograde axonal transport. Dynein is regulated by a number of protein complexes, notably by dynactin. Several studies have supported indirectly the involvement of dynein in neurodegeneration associated with Alzheimer's disease, Parkinson's disease, Huntington's disease and motor neuron diseases. First, axonal transport disruption represents a common feature occurring in neurodegenerative diseases. Second, a number of dynein-dependent processes, including autophagy or clearance of aggregation-prone proteins, are found defective in most of these diseases. Third, a number of mutant genes in various neurodegenerative diseases are involved in the regulation of dynein transport. This includes notably mutations in the P150Glued subunit of dynactin that are found in Perry syndrome and motor neuron diseases. Interestingly, gene products that are mutant in Huntington's disease, Parkinson's disease, motor neuron disease or spino-cerebellar ataxia are also involved in the regulation of dynein motor activity or of cargo binding. Despite a constellation of indirect evidence, direct links between the motor itself and neurodegeneration are few, and this might be due to the requirement of fully active dynein for development. Here, we critically review the evidence of dynein involvement in different neurodegenerative diseases and discuss potential underlying mechanisms.
细胞质动力蛋白 1（后称为动力蛋白）是一种主要的分子马达，它可以将线粒体、细胞器和蛋白质等货物朝着微管的负端移动。动力蛋白参与多种基本的细胞功能，如有丝分裂、自噬和内质网和高尔基体的结构，还参与神经元特定的功能，特别是逆行轴突运输。动力蛋白受许多蛋白质复合物的调节，特别是动力蛋白复合物。有几项研究间接支持动力蛋白参与与阿尔茨海默病、帕金森病、亨廷顿病和运动神经元疾病相关的神经退行性变。首先，轴突运输中断是神经退行性疾病的共同特征。其次，许多依赖动力蛋白的过程，包括自噬或聚集倾向蛋白的清除，在这些疾病中都存在缺陷。第三，各种神经退行性疾病中的许多突变基因都参与了动力蛋白运输的调节。这包括动力蛋白复合物 dynactin 的 P150Glued 亚基的突变，这些突变存在于 Perry 综合征和运动神经元疾病中。有趣的是，亨廷顿病、帕金森病、运动神经元病或脊髓小脑共济失调的基因突变产物也参与了动力蛋白运动活性或货物结合的调节。尽管有大量间接证据，但动力蛋白本身与神经退行性变之间的直接联系很少，这可能是由于动力蛋白完全活跃的发展要求。在这里，我们批判性地回顾了动力蛋白参与不同神经退行性疾病的证据，并讨论了潜在的潜在机制。
