KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons
Mingri Zhao,
Junling Wang,
Miao Liu,
Yaoyao Xu,
Jiali Huang,
Yiti Zhang,
Jianfeng He,
Ao Gu,
Mujun Liu,
Xionghao Liu
Affiliations
Mingri Zhao
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Junling Wang
Department of Neurology, Xiangya Hospital, Central South University, Changsha 410000, China
Miao Liu
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Yaoyao Xu
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Jiali Huang
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Yiti Zhang
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Jianfeng He
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Ao Gu
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Mujun Liu
Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410000, China
Xionghao Liu
MOE Key Lab. of Rare Pediatric Diseases, Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410000, China
Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.
