# Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $321,598

## Abstract

Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance
 PROJECT SUMMARY
 Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated
polycations essential for life. Dysregulation of polyamine metabolism has been observed to accompany several
neurological disease conditions include hypoxic and ischemic brain damage. However, the pathological
consequence of polyamine imbalance in the nervous system remains unclear. The pivotal role of polyamine
metabolism in the nervous system recently emerged with the mapping of causal mutation of Snyder-Robinson
Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes
the conversion of spermidine to spermine. SRS is the first confirmed genetic disorder associated with the
polyamine metabolic pathway. Neurological manifestations in SRS indicate the long-term pathological
consequence of polyamine imbalance, and provide a unique opportunity to uncover nervous system-specific
function of SMS and polyamine metabolism. We have established a Drosophila model for SRS and found that
human and Drosophila SMS proteins are functionally conserved, and loss of SMS in Drosophila recapitulated
several key features of SRS pathology, including polyamine imbalance, reduced survival rate, and synaptic
dysfunction. We discovered that SMS deficiency leads to excessive spermidine catabolism, and consequent
lysosomal dysfunction and oxidative stress in vivo. We hypothesize that spermidine/spermine imbalance due
to SMS deficiency causes altered polyamine catabolism, and that neutralizing the detrimental metabolites from
polyamine catabolism will ameliorate phenotypes and disease progression in SRS. In this application, we will
characterize the neuronal function of SMS in vivo, analyze the neurotoxicity resulted from polyamine
imbalance, study cellular phenotypes in SRS patient blood lymphoblast, skin fibroblast and bone BMSC cells,
and further discover genetic suppressors and potential pharmacological interventions for SRS. The proposed
work will provide significant and important insights into the function of polyamines and SMS, and delineate the
neuronal mechanisms underlying the neuropathology of spermine synthase-deficiency, and have long-lasting
and sustained impact on polyamine-associated neurological disorders.

## Key facts

- **NIH application ID:** 10445331
- **Project number:** 5R01NS109640-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Rong Grace Zhai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $321,598
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445331

## Citation

> US National Institutes of Health, RePORTER application 10445331, Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance (5R01NS109640-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10445331. Licensed CC0.

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