• Endoplasmic Reticulum Stress M...

*Result*: Endoplasmic Reticulum Stress Mediates Axon Initial Segment Shortening: Implications for Diabetic Brain Complications.

Title:
Endoplasmic Reticulum Stress Mediates Axon Initial Segment Shortening: Implications for Diabetic Brain Complications.
Authors:
Shelby JN; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA., Chisholm AM; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA., Akhmedov I; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA., Sheriff N; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA., Griggs RB; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA., Susuki K; Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA. keiichiro.susuki@wright.edu.
Source:
Journal of molecular neuroscience : MN [J Mol Neurosci] 2025 Dec 19; Vol. 76 (1), pp. 1. Date of Electronic Publication: 2025 Dec 19.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Humana Press Country of Publication: United States NLM ID: 9002991 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-1166 (Electronic) Linking ISSN: 08958696 NLM ISO Abbreviation: J Mol Neurosci Subsets: MEDLINE
Imprint Name(s):
Publication: Totowa, NJ : Humana Press
Original Publication: Boston : Birkhäuser [i.e. Cambridge, MA : Birkhäuser Boston, c1989-
MeSH Terms:
Axon Initial Segment*/drug effects , Axon Initial Segment*/metabolism , Diabetes Mellitus, Type 2*/metabolism , Diabetes Mellitus, Type 2*/complications , Endoplasmic Reticulum Stress*, eIF-2 Kinase/metabolism ; Phenylbutyrates/pharmacology ; Neurons/metabolism ; Neurons/drug effects ; Animals ; Mice ; Cells, Cultured ; Mice, Inbred C57BL
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Grant Information:
F30 NS124237 United States NS NINDS NIH HHS; R01 NS107398 United States NS NINDS NIH HHS; F30 NS124237 United States NH NIH HHS; R01 NS107398 United States NH NIH HHS
Contributed Indexing:
Keywords: Axon initial segment; Endoplasmic reticulum stress; Methylglyoxal; Protein kinase RNA-like ER kinase; Type 2 diabetes mellitus
Substance Nomenclature:
EC 2.7.11.1 (eIF-2 Kinase)
0 (Phenylbutyrates)
7WY7YBI87E (4-phenylbutyric acid)
Entry Date(s):
Date Created: 20251219 Date Completed: 20251219 Latest Revision: 20260127
Update Code:
20260130
PubMed Central ID:
PMC12717103
DOI:
10.1007/s12031-025-02448-y
PMID:
41417152
Database:
MEDLINE

*Further Information*

*Endoplasmic reticulum (ER) stress and activation of the three unfolded protein response pathways, in particular the protein kinase RNA-like ER kinase (PERK) pathway, contribute to the pathophysiology of various neurodegenerative conditions including type 2 diabetes mellitus (T2DM). T2DM is an increasingly prevalent metabolic disorder affecting millions. Even with strict glucose control, patients with T2DM frequently experience mild cognitive impairment and exhibit a significantly increased risk of developing dementia. We previously demonstrated that impaired cognitive flexibility is associated with shortening of axon initial segment (AIS) length in the prefrontal cortex in the T2DM model db/db mice. The AIS plays the crucial roles of regulation of action potential initiation and neuronal output. Even subtle shortening of AIS length can reduce excitability of neurons. In this study, we hypothesized that ER stress mediates AIS shortening in diabetic conditions. Utilizing primary mouse cortical cultures, we show that sodium 4-phenylbutyrate, a well-documented ER stress inhibitor, prevents AIS shortening and PERK activation induced by the T2DM factor methylglyoxal. Exposure of cortical cultures to an established ER stress inducer tunicamycin caused dose-dependent reduction of AIS length in the generalized population of the neurons without affecting neuronal viability. Co-exposure to a PERK-specific inhibitor GSK2606414 prevented AIS shortening induced by tunicamycin. These results demonstrate ER stress is sufficient and necessary for AIS shortening in vitro. Our findings identify ER stress and AIS shortening as potential therapeutic targets in T2DM-related cognitive impairment.
(© 2025. The Author(s).)*

*Declarations. Ethics approval: All animal procedures were approved by the Institutional Animal Care and Use Committee at Wright State University (Animal Use Protocol #1190). Competing interests: The authors declare no competing interests.*