# Neuronal PARP activity in fetal alcohol spectrum disorders

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $354,343

## Abstract

Fetal alcohol spectrum disorders (FASD) are the leading known and preventable causes of intellectual
disability. They impair executive functions including working memory, a function highly dependent on the
medial prefrontal cortex (mPFC). This brain region is one of the last to mature, the third trimester in humans
and the first 10 days after birth in rats. This is a vulnerable period for mPFC dendrites where their growth is
prone to disruption from environmental insults, such as ethanol (EtOH). Poly ADP ribose polymerases (PARP)
proteins are implicated in several cellular functions, including regulating gene expression. PARP synthesizes
and attaches poly (ADP-ribose) (PAR) chains (PARylating) to its targets. PARP enzymes can affect gene
expression by PARylating the epigenetic enzyme KDM4D. This reduces KDM4D’s ability to remove the
transcriptionally repressive, dimethylated lysine 9 at histone H3 (H3K9me2). PARP-mediated gene silencing
can also be accomplished by PARylating the transcription factor Peroxisome proliferator-activated
receptor gamma (PPARγ). Our underlying hypothesis is that EtOH induces PARP1 activity, promoting the
addition of PAR groups to known PARP1 targets such as PPARγ and KDM4D. This post-translational
modification would then reduce PPARγ and KDM4D’s ability to bind DNA or chromatin resulting in changes to
neurodevelopmental gene expression, dendritic arborization, and working memory. This hypothesis is
supported by our preliminary data in which EtOH increased PARP activity and reduced Bdnf IV, IXa, and Klf4
mRNA expression in primary cortical neuron cultures. These changes were reversible with a PARP inhibitor.
As a direct connection between PARP and PPARγ we found that PARP inhibition increased PPARγ binding to
Bdnf IV and Klf4 promoters in vitro. In vivo, neonatal EtOH treatment induced PARP activity, and this coincided
with a decrease in PPARγ DNA binding ability and reduced Bdnf IV mRNA expression. Thirty-one days after
the final dose, the reduction in Bdnf IV expression persisted in EtOH exposed rats. In the first aim, we plan to
dissect the molecular mechanisms connecting PARP to changes in developmental gene expression in the
mPFC with a focus on neuron-specific changes. In order to establish the role of PARP in EtOH induced Bdnf
and Klf4 gene expression silencing we will attempt to prevent expression changes by administering a PARP
inhibitor ABT-888 to EtOH treated rats. We will also dissect whether PARP mediated transcriptional repression
occurs via post-translational modifications to PPARγ and KDM4D using neuron cultures. In the second aim, we
will establish the role of PARP in the much-replicated deficits in mPFC dendritic arborization and
neuritogenesis observed in FASD models. In the third aim, we will study the role of PARP in third trimester
equivalent EtOH exposure-induced spatial working memory deficits. PARP inhibitors are known to be
neuroprotective, are currently undergoing clinical trials for other dis...

## Key facts

- **NIH application ID:** 10152472
- **Project number:** 5R01AA025035-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SUBHASH C. PANDEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $354,343
- **Award type:** 5
- **Project period:** 2017-05-20 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152472

## Citation

> US National Institutes of Health, RePORTER application 10152472, Neuronal PARP activity in fetal alcohol spectrum disorders (5R01AA025035-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152472. Licensed CC0.

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