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Biomedicines
Volume 12
Issue 8
10.3390/biomedicines12081693
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons

by
Mingri Zhao
1,
Junling Wang
2,
Miao Liu
1,
Yaoyao Xu
1,
Jiali Huang
1,
Yiti Zhang
1,
Jianfeng He
1,
Ao Gu
1,
Mujun Liu
3,4,5,* and
Xionghao Liu
1,4,5,*
1
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
2
Department of Neurology, Xiangya Hospital, Central South University, Changsha 410000, China
3
Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410000, China
4
Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha 410000, China
5
Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410000, China
*
Authors to whom correspondence should be addressed.
Biomedicines 2024, 12(8), 1693; https://doi.org/10.3390/biomedicines12081693 (registering DOI)
Submission received: 22 June 2024 / Revised: 17 July 2024 / Accepted: 23 July 2024 / Published: 30 July 2024
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
Versions Notes

Abstract

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.
Keywords: ALS; KIF1A; iPSC; motor neuron ALS; KIF1A; iPSC; motor neuron

Share and Cite

MDPI and ACS Style

Zhao, M.; Wang, J.; Liu, M.; Xu, Y.; Huang, J.; Zhang, Y.; He, J.; Gu, A.; Liu, M.; Liu, X. KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons. Biomedicines 2024, 12, 1693. https://doi.org/10.3390/biomedicines12081693

AMA Style

Zhao M, Wang J, Liu M, Xu Y, Huang J, Zhang Y, He J, Gu A, Liu M, Liu X. KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons. Biomedicines. 2024; 12(8):1693. https://doi.org/10.3390/biomedicines12081693

Chicago/Turabian Style

Zhao, Mingri, Junling Wang, Miao Liu, Yaoyao Xu, Jiali Huang, Yiti Zhang, Jianfeng He, Ao Gu, Mujun Liu, and Xionghao Liu. 2024. "KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons" Biomedicines 12, no. 8: 1693. https://doi.org/10.3390/biomedicines12081693

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