Age-related decline in nuclear envelope LINC complex drives neuronal aging via axon initial segment dysfunction
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.
Authors
- Sadafumi Suzuki
- Yasuyuki Ito (ORCID: https://orcid.org/0000-0001-9802-4673)
- Koichi Hasegawa (ORCID: https://orcid.org/0000-0002-9968-8129)
- Yasushi Okada (ORCID: https://orcid.org/0000-0003-2601-3689)
- Junpei Kondo
- Yuji Kurihara (ORCID: https://orcid.org/0000-0003-1309-1143)
- Yuki Fujita (ORCID: https://orcid.org/0009-0006-8347-3453)
- Kazuho Ikeda
- Noriyuki Hama
- Atsushi Toyoda (ORCID: https://orcid.org/0000-0002-0728-7548)
- Chiharu Takeda
- Michiaki Hamada (ORCID: https://orcid.org/0000-0001-9466-1034)
- Keiichiro Nakamura
- Mina Amemiya
- Ken-ichiro Kuwako (ORCID: https://orcid.org/0000-0002-1380-3035)
- Chao Zeng (ORCID: https://orcid.org/0000-0002-6130-2438)
Institutions
- National Institute of Genetics (JP)
- Waseda University (JP)
- Shimane University (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- Sanyo Women's College (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1038/s44319-026-00786-5
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Novartis Foundation
- Mitsui Sumitomo Insurance Welfare Foundation
- Japan Agency for Medical Research and Development
- Kawano Masanori Memorial Public Interest Incorporated Foundation
- Masato Kawano Memorial Public Interest Foundation for Promotion of Pediatrics
- Shimane University
- Mother and Child Health Foundation
- Daiwa Securities Health Foundation
- SENSHIN Medical Research Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Life Science Foundation of Japan
- Japan Society for the Promotion of Science
- Ube Foundation
- Core Research for Evolutional Science and Technology
- Moonshot Research and Development Program
- Harmonic Ito Foundation