Abstract:
Kinesin family member 2C (KIF2C)/mitotic centromere-associated kinesin (MCAK), is thought to be oncogenic as it is involved in tumour progression and metastasis. Moreover, it also plays a part in neurodegenerative conditions like Alzheimer\'s disease and psychiatric disorders such as suicidal schizophrenia. Our previous study conducted on mice demonstrated that KIF2C is widely distributed in various regions of the brain, and is localized in synaptic spines. Additionally, it regulates microtubule dynamic properties through its own microtubule depolymerization activity, thereby affecting AMPA receptor transport and cognitive behaviour in mice. In this study, we show that KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells results in abnormal gait, reduced balance ability and motor incoordination in male mice. These data suggest that KIF2C is essential for maintaining normal transport and synaptic function of mGlu1 and motor coordination in mice. KEY POINTS: KIF2C is localized in synaptic spines of hippocampus neurons, and regulates excitatory transmission, synaptic plasticity and cognitive behaviour. KIF2C is extensively expressed in the cerebellum, and we investigated its functions in development and synaptic transmission of cerebellar Purkinje cells. KIF2C deficiency in Purkinje cells alters the expression of metabotropic glutamate receptor 1 (mGlu1) and the AMPA receptor GluA2 subunit at Purkinje cell synapses, and changes excitatory synaptic transmission, but not inhibitory transmission. KIF2C regulates the transport of mGlu1 receptors in Purkinje cells by binding to Rab8. KIF2C deficiency in Purkinje cells affects motor coordination, but not social behaviour in male mice.
摘要:
驱动蛋白家族成员2C(KIF2C)/有丝分裂着丝粒相关驱动蛋白(MCAK),被认为是致癌的,因为它涉及肿瘤的进展和转移。此外,它也在神经退行性疾病,如阿尔茨海默病和精神疾病,如自杀性精神分裂症中发挥作用。我们先前对小鼠进行的研究表明,KIF2C广泛分布在大脑的各个区域,位于突触棘中。此外,它通过自身的微管解聚活性调节微管的动力学特性,从而影响小鼠的AMPA受体转运和认知行为。在这项研究中,我们显示KIF2C通过与Rab8结合调节浦肯野细胞中mGlu1受体的运输。Purkinje细胞中的KIF2C缺乏导致步态异常,降低雄性小鼠的平衡能力和运动不协调。这些数据表明KIF2C对于维持mGlu1的正常运输和突触功能以及小鼠的运动协调至关重要。关键点:KIF2C位于海马神经元的突触棘中,调节兴奋性传递,突触可塑性和认知行为。KIF2C在小脑中广泛表达,我们研究了其在小脑浦肯野细胞发育和突触传递中的功能。Purkinje细胞中的KIF2C缺乏改变了Purkinje细胞突触中代谢型谷氨酸受体1(mGlu1)和AMPA受体GluA2亚基的表达,改变兴奋性突触传递,但不是抑制性传播。KIF2C通过与Rab8结合调节浦肯野细胞中mGlu1受体的转运。Purkinje细胞中的KIF2C缺乏影响运动协调,但不是雄性小鼠的社会行为。