Association of variants in the KIF1A gene with amyotrophic lateral sclerosis  

作　　者：Panlin Liao Yanchun Yuan Zhen Liu Xiaorong Hou Wanzhen Li Jin Wen Kexuan Zhang Bin Jiao Lu Shen Hong Jiang Jifeng Guo Beisha Tang Zhuohua Zhang Zhonghua Hu Junling Wang 

机构地区：[1]Hunan Key Laboratory of Molecular Precision Medicine,Department of Critical Care Medicine,Xiangya Hospital,Central South University,Changsha 410008,China [2]Department of Neurology,Xiangya Hospital,Central South University,Changsha 410008,China [3]National Clinical Research Center for Geriatric Diseases,Xiangya Hospital,Central South University,Changsha 410008,China [4]Key Laboratory of Hunan Province in Neurodegenerative Disorders,Central South University,Changsha 410008,China [5]Center for Medical Genetics,School of Life Sciences,Central South University,Changsha 410008,China [6]Engineering Research Center of Hunan Province in Cognitive Impairment Disorders,Central South University,Changsha 410008,China [7]Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases,Changsha 410008,China [8]Hunan Provincial Clinical Research Center for Critical Care Medicine,Xiangya Hospital,Central South University,Changsha 410008,China [9]Hunan Key Laboratory of Animal Models for Human Diseases,School of Life Sciences,Central South University,Changsha 410008,China.

出　　处：《Translational Neurodegeneration》2022年第1期235-247,共13页转化神经变性病（英文）

基　　金：the National Key R&D Program of China(2021YFA0805200);the National Major Projects in Brain Science and Brain-like Research(2021ZD0201803 to J.W.);the National Natural Science Foundation of China(82171431,81671120,81300981 to J.W.,31872778 and 82171506 to Z.H.);the National Key Research and Development Program of China(#2018YFC1312003 to J.W.);the Natural Science Fund for Distinguished Young Scholars of Hunan Province,China(2020JJ2057 to J.W.);the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital(2020LNJJ13 to J.W.);Key Research and Development Programs from Hunan Province(2021DK2001 to Z.H.);the Innovative Team Program from Hunan Province(2019RS1010);the Innovation-driven Team Project from Central South University(2020CX016);the Discipline Innovative Engineering Plan(111 Program)of China(B13036).Z.H.is supported by the Hunan Hundred Talents Program for Young Outstanding Scientists.

摘　　要：Background:Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord.As in many other neurodegenerative disorders,the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport.Notably,sen-sory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2(HSAN2)and spastic paraplegia 30(SPG30)share several causative genes with ALS,as well as having common clinical phenotypes.KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors(SVPs)and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.Methods:Here,we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.Results:We identified rare damage variants(RDVs)in the KIF1A gene associated with ALS and delineated the clini-cal characteristics of ALS patients with KIF1A RDVs.Clinically,these patients tended to exhibit sensory disturbance.Interestingly,the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein.Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A,VAMP2,and synaptophysin.Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.Conclusions:Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS,indicating KIF1A as an important player in the oligogenic scenario of ALS.

关 键 词：Amyotrophic lateral sclerosis KIF1A Axonal transport Presynaptic vesicle precursors 

分 类 号：R746.4[医药卫生—神经病学与精神病学]