# Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD

> **NIH NIH P01** · UNIVERSITY OF KENTUCKY · 2020 · $131,829

## Abstract

Lafora disease (LD) is a fatal, recessive neurodegenerative disorder that presents as an epileptic event in 
the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic, hyperphosphorylated, water- 
insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes 
encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, and mutations in either gene results 
in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy 
perturbations. Associated with LB formation, cells display multiple markers indicating perturbations in critical 
cellular pathways, including increased endoplasmic reticulum stress, autophagy, ROS production, and others. 
 The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): 
which is an international collaboration devoted to the Diagnosis, Treatment, and Cure of LD. The goals of this 
project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish 
therapeutic options. To achieve these goals, we will define the molecular basis of LD utilizing structural 
biochemistry, cellular biology, and mouse models and translate our insights into mutation-specific diagnoses 
and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD. 
 We will first utilize integrated structural and functional tools to define the physical and cellular perturbations 
caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of 
neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and 
treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further, we will 
determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to 
treatment of symptoms with antiepileptic drugs. Lastly, we will establish the beneficial effect of pharmacological 
intervention novel compounds that promote read-through of premature termination codons. Embedded in these 
approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of 
molecular sub-types of the disease, key to each of the LECI Center projects. Further, these results have 
significant broader implications since LD is one of five major progressive myoclonic epilepsies, and the 
connection between metabolic dysfunction and epilepsy is an emerging theme. 
 Cumulatively, these results will allow personalized therapeutic options that are developed to promote 
recovery of molecular and cellular function as a means of treating and curing LD.

## Key facts

- **NIH application ID:** 9989205
- **Project number:** 5P01NS097197-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Matthew S. Gentry
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $131,829
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989205

## Citation

> US National Institutes of Health, RePORTER application 9989205, Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD (5P01NS097197-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989205. Licensed CC0.

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