# Use of IPSC to define role of astrocytes in specifying risk for onset of cerebral adrenoleukodystrophy

> **NIH NIH R56** · HENRY FORD HEALTH SYSTEM · 2020 · $376,250

## Abstract

PROJECT SUMMARY/ABSTRACT
The mechanism of onset of neuroinflammation in fatal phenotypes in males with inherited X-linked
adrenoleukodystrophy (X-ALD) disease remains unknown. 60% of male X-ALD patients develop fatal cerebral
neuroinflammation (cALD) while remaining develop milder adrenomyeloneuropathy (AMN) characterized by
axonopathy without neuroinflammation. The primary genetic defect in X-ALD (mutation/deletion in ABCD1 gene)
and the biochemical defect (accumulation of very long chain fatty acid; C>22:0 in plasma and tissues) cannot
predict the onset of AMN or cALD. Our long-term goal is to dissect the molecular mechanism underlying
differential phenotype development in X-ALD. The objective of this application is to identify metabolic pathways
that underlie the differential neuroinflammatory response in AMN and cALD human astrocytes. These astrocytes
were differentiated from induced pluripotent stem cells (iPSCs), which in turn were generated by reprogramming
of human control, AMN and cALD patient-derived fibroblasts. Metabolic reprogramming is emerging as a novel
regulator of inflammatory response. Astrocytes rely on mitochondrial respiration (OXPHOS) for their metabolic
needs but switch to glycolysis under neuroinflammatory environment to boost biosynthetic pathways to produce
inflammatory mediators. Our preliminary proof-of-concept data, with untargeted metabolomics, identified
metabolites altered between healthy-control and cALD phenotype postmortem brain. Within the cALD brain white
matter, unique metabolite changes were recorded between distant normal looking areas and areas adjacent to
the plaque suggesting an association with disease progression. We found both OXPHOS and glycolysis
decreased (low metabolic state) in human cALD astrocytes despite higher inflammatory response. This low
metabolic state suggests role of novel alternative source(s) of fuel driving the neuroinflammatory response in
cALD astrocytes. Our central hypothesis is that metabolic reprogramming in cALD astrocytes drives their
proinflammatory shift that underlies the neuroinflammatory disease progression in cALD. To test our hypothesis
we propose two specific aims: 1) To elucidate the metabolic reprogramming responsible for inflammatory
response in cALD astrocytes. 2) To determine if dysfunctional mitochondria play a role in inflammatory nature
of cALD astrocytes? We will take advantage of control, AMN and cALD astrocytes generated from iPSC’s in our
laboratory for these studies. This proposal is innovative, because it departs from the status quo by identifying for
the first time, metabolic pathways differentially regulating inflammatory response in human AMN and cALD
astrocytes. The proposed research is significant because the cellular mechanism(s) that lead to less severe
AMN or fatal cALD phenotype in response to same ABCD1 mutation remain unknown even four decades after
the identification of gene defect in X-ALD. Impact: With the rising rate of newly diagnosed c...

## Key facts

- **NIH application ID:** 10118513
- **Project number:** 1R56NS114245-01
- **Recipient organization:** HENRY FORD HEALTH SYSTEM
- **Principal Investigator:** Jaspreet Singh
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 1
- **Project period:** 2020-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118513

## Citation

> US National Institutes of Health, RePORTER application 10118513, Use of IPSC to define role of astrocytes in specifying risk for onset of cerebral adrenoleukodystrophy (1R56NS114245-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10118513. Licensed CC0.

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