Dr. Emmanuel Ortiz

Institution: Pontificial Catholic University of PR

Email: emmanuel_cruz@pucpr.edu

The Metabolomic Profile of the Angelman Syndrome Brain

Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and neurological symptoms like ataxia and epilepsy, associated with the loss of expression of the maternal allele of the Ube3a gene, a ubiquitin ligase regulating protein degradation (Bird, 2014). Although AS has been associated to hippocampal mitochondrial dysfunction (Santini et al., 2015), no study has targeted metabolic pathways dysregulated by this illness. Previous studies found that hippocampal and cerebellar metabolism are critical for cognitive functions such as memory formation (Suzuki et al., 2011; Hoshino et al., 2016), making brain metabolism an interesting new target to study the cognitive deficits associated with AS. In this study, we hypothesize that deletion of the maternal allele of Ube3a results in metabolic dysregulations that lead to the impairments associated with AS. To address this hypothesis, we designed two specific aims using a mouse model that displays all the symptoms of AS (Cruz et al., 2020): Aim 1: To examine the hippocampal and cerebellar metabolome of young and adult AS mice. I will examine the hippocampal and cerebellar metabolome of AS mice compared to wild-type (W T) controls using a metabolomics. In addition to examine differences between AS mice an WT controls, our studies will be performed in young (6 weeks old) and adult (12 weeks old) mice to examine age-related differences. Aim 2: To examine the hippocampal and cerebellar proteome of young and adult AS mice. We will examine the proteome of the hippocampus and cerebellum in young and adult AS mice compared to controls using proteomics. This will allow us to identify protein pathways affected by AS at different ages. This data will be independent of the data from Aim 1. However, we will also perform an OMICs integration analysis and combine the metabolomics data of Aim 1 with the proteomics data of Aim 2. For the proteomics analysis, we will focus on the levels of metabolic enzymes to develop the full metabolic profile of the AS brain compared to controls. The data of non-metabolic proteins will also be examined and used as preliminary data for future studies.