Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction.
A correction to this paper has been published: the notice, 42527630, from Europe PMC.
Overview
- Department of Neural and Muscular Physiology, School of Medicine, Shimane University,Izumo, Japan
- Present Address: Department of Clinical Laboratory Science, Sanyo Women’s College,Hiroshima, Japan
- Faculty of Science and Engineering, Waseda University,Tokyo, Japan
- Department of Developmental Biology, School of Medicine, Shimane University,Izumo, Japan
- Department of Cell Biology, Graduate School of Medicine, The University of Tokyo,Tokyo, Japan
- Laboratory for Cell Polarity Regulation, RIKEN Center for Biosystems Dynamics Research (BDR),Osaka, Japan
- Department of Physics, Graduate School of Science, The University of Tokyo,Tokyo, Japan
- Universal Biology Institute (UBI), The University of Tokyo,Tokyo, Japan
- International Research Center for Neurointelligence (WPI-IRCN), Institutes for Advanced Study, The University of Tokyo,Tokyo, Japan
- Comparative Genomics Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics,Mishima, Japan
- AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology,Tokyo, Japan
Abstract
Brain aging is an intricate process that inevitably leads to functional deterioration. However, its molecular drivers remain unclear. Here, we show that the age-related decline in LINC complex expression on the neuronal nuclear envelope impairs axon initial segment (AIS)-mediated excitability and triggers brain aging. With aging, the expression of LINC complex components, including Sun1, decreases in various brain regions, accompanied by a reduction in AIS length. Preserving Sun1 expression rescues nuclear structural abnormalities in aged neurons, shifting chromatin dynamics and global gene expression toward those of young neurons. Particularly, it restores the expression of AIS-related molecules, including voltage-gated sodium or potassium channels essential for action potential generation. Inhibiting the LINC complex in young mice impairs AIS integrity, leading to reduced neuronal excitability and brain dysfunction. Furthermore, Sun1 administration to aged neurons prevents age-related AIS shortening, excitability impairment, and brain function changes. Thus, we uncover the mechanism of normal brain aging involving AIS dysfunction, identifying the LINC complex component Sun1 as essential for preserving brain function.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- figshare:28827575, at figshare; found in “Data availability”
Other data links
- ebi.ac.uk/
biostudies/ , EMBL-EBI; found in the notessourcedata
Data availability
The Hi-C and RNA-seq data sets are deposited in the DNA Data Bank of Japan under BioProject accession number PRJDB18989. These data are available at: https://
The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_103
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 3 keywords, 11 MeSH terms, 16 funders, 85 references, 54 RRIDs, 1 integrity notice.
Cite
This paper
Hasegawa, K., Hama, N., Amemiya, M., Zeng, C., Ito, Y., Suzuki, S., Nakamura, K., Kondo, J., Takeda, C., Kurihara, Y., Ikeda, K., Fujita, Y., Okada, Y., Toyoda, A., Hamada, M., & Kuwako, K.-i. (2026). Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction. EMBO reports, 27(13), 3788-3825. https://
BibTeX
@article{hasegawa2026age
author = {Hasegawa, Koichi and Hama, Noriyuki and Amemiya, Mina and Zeng, Chao and Ito, Yasuyuki and Suzuki, Sadafumi and Nakamura, Keiichiro and Kondo, Junpei and Takeda, Chiharu and Kurihara, Yuji and Ikeda, Kazuho and Fujita, Yuki and Okada, Yasushi and Toyoda, Atsushi and Hamada, Michiaki and Kuwako, Ken-ichiro},
title = {{Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction}},
journal = {EMBO reports},
year = {2026},
month = may,
volume = {27},
number = {13},
pages = {3788--3825},
publisher = {Nature Publishing Group},
issn = {1469-221X},
doi = {10.1038/
url = {https://
pmid = {42174181},
pmcid = {PMC13354796}
}
RIS
TY - JOUR
AU - Hasegawa, Koichi
AU - Hama, Noriyuki
AU - Amemiya, Mina
AU - Zeng, Chao
AU - Ito, Yasuyuki
AU - Suzuki, Sadafumi
AU - Nakamura, Keiichiro
AU - Kondo, Junpei
AU - Takeda, Chiharu
AU - Kurihara, Yuji
AU - Ikeda, Kazuho
AU - Fujita, Yuki
AU - Okada, Yasushi
AU - Toyoda, Atsushi
AU - Hamada, Michiaki
AU - Kuwako, Ken-ichiro
TI - Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction
T2 - EMBO reports
J2 - EMBO Rep
PY - 2026
DA - 2026/
VL - 27
IS - 13
SP - 3788
EP - 3825
SN - 1469-221X
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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