# The Role of UBE3A Isoforms in AS-associated Seizure Susceptibility

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $40,064

## Abstract

Abstract
Recurring and debilitating seizures affect ~90% of individuals with Angelman syndrome (AS), a
neurodevelopmental disorder further characterized by intellectual disability, sleep disruption, and ataxia. These
seizures are often refractory to commonly prescribed antiepileptic drugs, whose side effects can exacerbate
other AS symptoms. As a result, AS-associated seizures are consistently ranked as one of the most
challenging aspects of AS by caretakers and physicians. AS is caused by a loss of the maternally inherited
UBE3A allele because the paternally inherited UBE3A allele is epigenetically silenced in neurons, resulting in a
complete loss of UBE3A protein in all neurons. Previous preclinical therapeutic strategies and current clinical
trials have shown some promise by re-expressing UBE3A in neurons, but these efforts face several delivery
and toxicity challenges that may limit their clinical development. Therefore, it is necessary to identify other
novel treatment strategies to mitigate seizures in AS. UBE3A is an E3 ubiquitin ligase that targets substrates
for proteasomal degradation and consists of two main isoforms – short-UBE3A and long-UBE3A.
Dysregulation of UBE3A isoform substrates underlies AS symptoms. Indeed, each isoform may have distinct
cellular and phenotypic contributions to AS symptoms due to their unique N-termini, protein levels, and
subcellular localizations. However, how each UBE3A isoform and their respective substrates contributes to AS
epileptogenesis remains unclear. Such knowledge could suggest novel therapeutic avenues for treating
refractory AS-associated epileptogenesis. Accordingly, in the current proposal I will use two seizure models to
establish the contribution of each UBE3A isoform to AS seizure susceptibility (Aim 1), and I will use a proximity
ligation assay to define isoform-specific UBE3A substrates in a cell type that drives seizure susceptibility in AS
model mice (Aim 2). My work will thus identify the contribution of each UBE3A isoform and their respective
substrates to epilepsy in AS, enabling future pharmacological targeting that may overcome the limitations of
current therapeutic efforts.

## Key facts

- **NIH application ID:** 10994498
- **Project number:** 1F31NS139445-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Joseph Krzeski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,064
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994498

## Citation

> US National Institutes of Health, RePORTER application 10994498, The Role of UBE3A Isoforms in AS-associated Seizure Susceptibility (1F31NS139445-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10994498. Licensed CC0.

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