Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors
Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors
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DOI：
10.1073/pnas.1905690116
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发表时间：
2019-09-10
影响因子：
11.1
通讯作者：
Niwa, Shinsuke
中科院分区：
文献类型：
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作者：
Chiba, Kyoko;Takahashi, Hironori;Niwa, Shinsuke
KIF 1A是一种驱动蛋白家族马达，参与突触囊泡前体（SVP）沿着微管（MT）的轴突运输。在人类中，KIF 1A中超过10个点突变与运动神经元疾病遗传性痉挛性截瘫（SPG）相关。然而，并非所有这些突变似乎都抑制KIF 1A运动的运动性，因此KIF 1A突变如何导致神经病变的令人信服的分子解释是不可用的。在这项研究中，我们建立了在体外运动与纯化全长人KIF 1A的测定，并发现KIF 1A突变与遗传性SPG导致KIF 1A运动的过度激活。将相应的突变引入秀丽隐杆线虫KIF 1A同源物unc-104中，揭示了SVP在轴突尖端的异常积累和SVP的顺行轴突运输增加。我们的数据表明，驱动蛋白运动活动的过度激活，而不是其功能的丧失，是人类运动神经元疾病的原因。
KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in KIF1A are associated with the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs. Our data reveal that hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease in humans.