# Metabolic Mechanisms of Copper-Dependent Neurodegeneration and Excitability in Menkes Disease

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Menkes disease is a rare genetic condition in which the disruption of copper homeostasis induces
neurodegeneration and other neurological symptoms soon after birth. The underlying mechanisms of Menkes
neuropathology remain unclear, but the metabolic changes observed in Menkes disease and the crucial role of
mitochondria in neurons point to dysregulation of cellular bioenergetics as a possible factor. Preliminary data in
human cells indicates that copper depletion decreases expression of genes regulated by hypoxia induced factor
1 alpha (HIF-1α). HIF-1α is a transcription factor sensitive to metals and oxygen that regulates cellular
bioenergetics by switching metabolism from mitochondrial oxidative phosphorylation to glycolysis. Further, these
copper depleted cells exhibit increased mitochondrial respiration. Resolving the newly identified role of HIF-1α
in regulating mitochondrial function is central to understanding how copper dyshomeostasis elicits
neurodegeneration in Menkes disease. Thus, the overall objective of this F31 NRSA application is to test how
copper depletion influences the HIF-1α pathway in neurons to regulate cellular metabolism and influence cell
excitability and survival. The central hypothesis that will be tested in this proposal is that neuronal copper
depletion selectively downregulates transcriptional activity of the HIF-1α pathway to redirect nutrients through
mitochondrial respiration rather than glycolysis, rendering cells hyperexcitable due to production of reactive
oxygen species by mitochondria and thus susceptible to cell death. In Aim 1, the HIF-1α pathway will be
stimulated in copper depleted and control neuroblastoma cells or primary cultured neurons in order to
comprehensively assess gene expression, determine binding of HIF-1α to target genes, and quantify
mitochondrial respiration and glycolysis in the context of HIF-1α activity. In Aim 2, genetically encoded calcium
indicators will be used in primary neuronal cultures from wildtype or neuronal-specific copper depleted mice while
stimulating the HIF-1α pathway to assess how copper depletion affects cell excitability and determine the effect
of HIF-1α on these phenotypes. Completion of these aims will clarify the metabolic pathways responsive to
copper and their effects on neuronal function. The application of this knowledge will inform our understanding,
research, and treatment of neuropathology of diseases known to be associated with dysregulated metals and/or
metabolism for which there are currently limited therapeutics.

## Key facts

- **NIH application ID:** 10934342
- **Project number:** 5F31NS127419-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Alicia R Lane
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2022-04-06 → 2025-04-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934342

## Citation

> US National Institutes of Health, RePORTER application 10934342, Metabolic Mechanisms of Copper-Dependent Neurodegeneration and Excitability in Menkes Disease (5F31NS127419-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10934342. Licensed CC0.

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