# ER stress mediates methylglyoxal-evoked AIS shortening and neuronal dysfunction

> **NIH NIH R01** · WRIGHT STATE UNIVERSITY · 2020 · $40,577

## Abstract

PROJECT SUMMARY/ABSTRACT (Diversity Supplement)
 Alterations in the axon initial segment (AIS) are key pathophysiologies in various neurodegenerative
diseases, including diabetes. Shortening of AIS length has been shown to lower neuronal excitability and is
also implicated in cognitive impairment in type 2 diabetes and Alzheimer's disease. However, the cellular and
molecular mechanisms of how these domains are altered in disease conditions remain poorly understood. This
critical gap in knowledge limits the field's ability to manipulate the AIS for treatment. In order to fill this
significant gap in our knowledge, the parent grant (R01 NS107398) tests the hypothesis that methylglyoxal
(MG) disrupts AIS protein complexes via calpain activation and inhibits nervous system function. The current
diversity supplement proposal seeks to elucidate more detailed mechanisms that lead to AIS shortening. The
overall objective of this application is to identify a critical cellular mechanism that activates calpains in response
to MG increase. The prior studies and preliminary data provided here have identified endoplasmic reticulum
(ER) stress as a potential mediator for calpain activation and AIS shortening induced by MG increase. The
hypothesis is that sublethal increase of MG induces ER stress, leading to calpain activation and AIS shortening.
We will test this hypothesis via two Specific Aims. Aim 1: Test the hypothesis that, independent of MG increase,
sublethal levels of ER stress cause calpain activation, AIS shortening, and neuronal network dysfunction. Aim
2: Test the hypothesis that inhibition of ER stress prevents MG-induced calpain activation, AIS shortening, and
neuronal network dysfunction. This application is conceptually innovative, as we propose that ER stress is a
key mediator of AIS shortening and neuronal dysfunction induced by MG. Innovative use of multi-electrode
arrays will determine the effects of induced ER stress and increased MG together with ER stress inhibition on
neural network function. The proposed research is significant, because completion of the aims will validate ER
stress as potential targets for translational research aimed at treatments for comorbid cognitive impairment in
type 2 diabetes. These results also have potential to impact a wide variety of neurodegenerative conditions,
such as Alzheimer's. In addition to the scientific work, the important aspect of this diversity supplement is to
support the career development of an African American female MD/PhD student. Her career goal is an
independent physician scientist studying changes in neural transmission and cognitive defects caused by
neurodegenerative diseases. Cognitive disorders disproportionately affect African Americans, yet African
Americans are underrepresented in the scientific workforce. To address the inequity in heath research and
clinics, it is critical to diversify the field. Thus, the proposed work and mentoring activities in this diversity
supplement wi...

## Key facts

- **NIH application ID:** 10055833
- **Project number:** 3R01NS107398-01A1S1
- **Recipient organization:** WRIGHT STATE UNIVERSITY
- **Principal Investigator:** Keiichiro Susuki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,577
- **Award type:** 3
- **Project period:** 2020-01-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055833

## Citation

> US National Institutes of Health, RePORTER application 10055833, ER stress mediates methylglyoxal-evoked AIS shortening and neuronal dysfunction (3R01NS107398-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10055833. Licensed CC0.

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