Abstract Details

Title Contributions of Purine Synthesis and Recycling During Brain Development: Relevance to Lesch Nyhan Disease

Topic Child Neurology and Developmental Neurology

Presentation(s) S39 - Child Neurology and Developmental Neurology (5:06 PM-5:18 PM)

Poster/Presentation
Number 009

Background Purines are important components of nucleic acids and are crucial for cell development, cell signaling and energy consumption. There are two main pathways to make purines, purine salvage via hypoxanthine-guanine phosphoribosyl transferase (HPRT1) and de novo synthesis of new purines. HPRT1 mutation is associated with developmental brain problems in LND.

Objective

This study sought to determine the relative importance of the two major sources of purines during neural development, and the consequence of the lack of purine salvage in Lesch Nyhan disease (LND).

Design/Methods We differentiated human derived induced pluripotent stem cell (iPSC) lines from subjects with LND and healthy controls into neurons using a mono-layer induction protocol. We evaluated gene expression for HPRT1 and 3 enzymes of the de novo pathway (phosphoribosyl pyrophosphate amidotransferase, PPAT; glycinamide ribonucleotide transformylase, GART; and phosphoribosylformylglycinamidine synthase, PFAS) on Day 0 (iPSC), Day 15 (neuroprogenitor or NPC), Day 45 (immature neuron), day 60 (mature neuron).

Results

In control, HPRT1 and all 3 de novo enzymes were highest at Day 0 and progressively declined with neuronal maturation. In LND, HPRT1 remained low or undetectable at all time points. Also for LND, all 3 de novo enzymes were increased relative to controls at all time points. However, the ratio of each de novo enzyme to HPRT1 revealed a marked decline with neuronal maturation.

Conclusions

All sources of purines decline with neurodevelopment. The ratio of salvage to synthesis increases with neurodevelopment, implying maturing neurons are increasingly dependent on salvage for purines. HPRT1 mutation in LND is associated with relatively high levels of de novo enzymes in iPSCs, presumably as a compensatory strategy. However, this compensation seems to decline in more mature neurons.

Authors/Disclosures
Fatemeh Seifar (Emory University) PRESENTER	Ms. Seifar has nothing to disclose.
	No disclosure on file
	No disclosure on file
H. A. Jinnah, MD, PhD, FAAN (Emory University)	Dr. Jinnah has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takaha/Ene. Dr. Jinnah has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ipsen. Dr. Jinnah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ipsen. Dr. Jinnah has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. The institution of Dr. Jinnah has received research support from Addex. The institution of Dr. Jinnah has received research support from Aeon. The institution of Dr. Jinnah has received research support from Revance. The institution of Dr. Jinnah has received research support from Jazz.