# Clues from a rare neurodegenerative disease towards target identification for diabetes mellitus

> **NIH NIH SC2** · ST. JOHN'S UNIVERSITY · 2020 · $164,000

## Abstract

Project Summary/Abstract:
Lafora disease (LD) is a glycogen metabolic disorder that manifests itself as
neurodegenerative epilepsy. A pathological hallmark of LD is the accumulation of
abnormal insoluble glycogen that resembles plant starch in various organs including
brain. LD occurs due to autosomal recessive mutations in genes encoding proteins laforin
and malin. Laforin is a dual-specificity phosphatase and malin is an E3 ubiquitin ligase.
Multiple studies in LD field have shown that laforin functions as a phosphatase for
glycogen. Malin forms a functional complex with laforin and malin alone or the laforin-
malin complex is known to ubiquitinate multiple proteins involved in glycogen
metabolism. Hormones insulin and glucagon tightly control blood glucose homeostasis
by their effect on glucose transport and storage. In type-2 diabetes, defects in insulin
responsiveness leads to a state called insulin resistance. Few studies in LD research have
looked at insulin response in LD knockout animals. One study found that laforin
knockout mice had enhanced insulin response by PI3K-Akt pathway that led to increased
glucose transport and glycogen synthesis. However, another study, with better-matched
genetic background for the wildtype and knockout mice, observed that insulin response
was normal in both laforin and malin knockout mice. In addition, a study using
knockdown of laforin and malin in cell culture showed that glucose transporters
translocate to cell membrane in cells lacking laforin or malin and that these cells have
higher glucose uptake. LD patients die in the second decade of life and therefore a
pathophysiological correlation of LD and diabetes is absent. Moreover, ubiquitin
posttranslational modification of glycogen-metabolic proteins has not been studied in
diabetes pathophysiology. Our proposal will study the effect of hormones and nutrients
on novel glycogen metabolic proteins- laforin and malin in physiology and diabetes
pathophysiology. Any defects in the expression, signaling, and function of these proteins
in diabetes will provide us with targets to regulate glucose storage. The proposal is highly
relevant in our understanding of glycogen metabolic disorders and diabetes mellitus.

## Key facts

- **NIH application ID:** 9850982
- **Project number:** 5SC2GM125550-03
- **Recipient organization:** ST. JOHN'S UNIVERSITY
- **Principal Investigator:** Vikas Vasudeo Dukhande
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,000
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850982

## Citation

> US National Institutes of Health, RePORTER application 9850982, Clues from a rare neurodegenerative disease towards target identification for diabetes mellitus (5SC2GM125550-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850982. Licensed CC0.

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