Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human

The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transports numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo b...

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Bibliographic Details
Published in:Molecular neurobiology 2021-09, Vol.58 (9), p.4376-4391
Main Authors: Fu, Xiaolong, An, Yachun, Wang, Hongyang, Li, Peipei, Lin, Jing, Yuan, Jia, Yue, Rongyu, Jin, Yecheng, Gao, Jiangang, Chai, Renjie
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cochlea
Cytoplasm
Down-regulation
Genomes
Hair cells
Hair Cells, Auditory - metabolism
Hearing loss
Hearing Loss, Sensorineural - genetics
Hearing Loss, Sensorineural - metabolism
Humans
Kinesin
Kinesins - genetics
Kinesins - metabolism
Localization
Mice
Mice, Knockout
Microtubules - metabolism
Mitochondria
Mitochondria - metabolism
Neurobiology
Neurology
Neurosciences
Protein transport
Whole genome sequencing
γ-Aminobutyric acid A receptors
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Summary:The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transports numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo binding and regulates kinesin-1 motility, is essential for cochlear function. We generated mice lacking Klc2, and they suffered from low-frequency hearing loss as early as 1 month of age. We demonstrated that deficiency of Klc2 resulted in abnormal transport of mitochondria and the down-regulation of the GABAA receptor family. In addition, whole-genome sequencing (WGS) of patient showed that KLC2 was related to low-frequency hearing in human. Hence, to explore therapeutic approaches, we developed adeno-associated virus containing the Klc2 wide-type cDNA sequence, and Klc2-null mice delivered virus showed apparent recovery, including decreased ABR threshold and reduced out hair cell (OHC) loss. In summary, we show that the kinesin transport system plays an indispensable and special role in cochlear HC function in mice and human and that mitochondrial localization is essential for HC survival.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-021-02422-w