# Glycogen promotes protein aggregation in ALS and FTD

> **NIH NIH R21** · MAYO CLINIC  JACKSONVILLE · 2022 · $430,375

## Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are genetically-related
neurodegenerative diseases pathologically characterized by aggregation of proteins, such as TDP-43, FUS,
SOD1, hnRNPs, dipeptide protein repeats, Tau, etc. How these proteins aggregate is unclear—many factors
seem to be at play. However, whether and how sugar molecules play a role in this process is unknown.
In vitro studies suggested molecular crowding agents, such as dextran, promote the condensation of some of
the aforementioned ALS/FTD proteins and induce their aggregation. Given the structural similarity between
dextran and glycogen, both of which are polymers of glucose, we propose an intriguing hypothesis that
glycogen can function as a crowding agent to induce ALS/FTD protein aggregation, thereby contributing to
neurodegeneration. Importantly, glycogen, but not dextran, is a naturally present polysaccharide in mammals,
suggesting its role as a crowding agent in physiological conditions. Consistent with this hypothesis, previous
studies suggested that glycogen is abnormally upregulated and/or accumulated in ALS/FTD patients and
animal models, and our preliminary data suggest that suppressing glycogenosis ameliorate neurodegeneration
in a Drosophila model of ALS/FTD. Therefore, we are excited about this hypothesis and propose to further test
it in vitro, using recombinant proteins, and in cultured cells and disease models, as well as to verify it in human
patients. The proposed studies will reveal the first mechanistic connection between polysaccharide and protein
aggregation in ALS and FTD. Importantly, since both glycogen upregulation/accumulation and protein
aggregation are implicated in aging and other neurodegenerative diseases, our study may identify a common
mechanism by which defects in sugar metabolism contribute to aging and age-related diseases.

## Key facts

- **NIH application ID:** 10422901
- **Project number:** 1R21NS127331-01
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Yongjie Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2022-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422901

## Citation

> US National Institutes of Health, RePORTER application 10422901, Glycogen promotes protein aggregation in ALS and FTD (1R21NS127331-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10422901. Licensed CC0.

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