# Molecular mechanisms of the ADPRHL2-mediated pediatric neurodegenerative disease

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $39,970

## Abstract

PROJECT SUMMARY
 ADP-ribosylation is a posttranslational modification of proteins characterized by the addition of poly-
ADP-ribose (PAR) in response to cellular stressors, such as excitotoxicity or oxidative stress.1 The PAR
Polymerase (PARP) family catalyzes this reaction, which is reversed by two known factors, Poly-ADP Ribose
Glycohydrolase (PARG) and ADP-ribosylhydrolase-like protein 2 (ADPRHL2).1 Using genome-wide linkage
analysis and exome sequencing, inactivating mutations in ADPRHL2 have been identified in several large
consanguineous families. The patients exhibit a pediatric onset neurodegenerative disorder with brain atrophy
and sudden death from epilepsy. Previous studies have identified ADPRHL2 as the only active glycohydrolase
present in mitochondria; however, its importance and role in the mitochondria remain understudied. The goal is
to describe this clinical condition as a new syndrome cause of neurodegeneration and study oxidative-stress
induced mechanisms by which loss of ADPRHL2 promotes cell death both in vitro and in vivo. The generation
of iPSCs from patient fibroblasts, which can be further reprogrammed into a neural differentiation lineage,
offers an exciting and relevant tool to test our model. First, the effect of the patient mutations on cellular and
protein function in both patient neurons and CRISPR knockout mice mimicking these mutations will be
determined. Second, the effects of loss of ADPRHL2 on mitochondrial function will be assessed with the help
of an established collaboration with Dr. Gulcin Pekkurnaz's mitochondrial lab at UCSD. A collaboration with Dr.
Gabriel Haddad's hypoxia fly lab at UCSD has already been established to generate a Drosophila model to test
the evolutionary conservation of function of this gene. Third, pharmacological manipulation of the PARP
pathway will be used to rescue the phenotypes both in vitro and in vivo in hopes of developing a treatment for
this novel pediatric disease. The outcome of this work will not only provide novel insight into mitochondrial
function, but will also identify potential treatments for a new early-onset neurodegenerative disease.
Hypothesis: Mutations in ADPRHL2 lead to increased vulnerability to neuronal death in response to oxidative
stress. Failed PAR hydrolysis due to absence of ADPRHL2 in the mitochondria leads to bioenergetic failure,
ultimately triggering apoptosis.
Aim 1: Test the hypothesis that ADPRHL2 patient mutations interfere with protein function and PARylation of
mitochondrial proteins.
Aim 2: Test the hypothesis that loss of ADPRHL2 leads to stress-induced defects in mitochondrial function and
cell survival.
Aim 3: Test the hypothesis that loss of ADPRHL2 can be pharmacologically or genetically rescued by
inhibiting PARP activity in vitro and in vivo.

## Key facts

- **NIH application ID:** 9928448
- **Project number:** 5F31HD095602-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Shereen G. Ghosh
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,970
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928448

## Citation

> US National Institutes of Health, RePORTER application 9928448, Molecular mechanisms of the ADPRHL2-mediated pediatric neurodegenerative disease (5F31HD095602-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928448. Licensed CC0.

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