# Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $1,724,424

## Abstract

The overall goal of this proposal is to elucidate the thiol redox mechanisms that alter neurodevelopment,
which can exacerbate cognitive dysfunction in Down syndrome (DS). Down syndrome (DS) is the most
common genetic cause of intellectual disability. Importantly, the extent of intellectual disability is highly variable,
and parents of affected individuals are often aware of DS during pregnancy. This creates a window of opportunity
to improve outcomes through identification of environmental factors and associated mechanisms impacting early
development in DS. Preliminary data and reports from our laboratory and others demonstrate that cells from DS
individuals exhibit distorted proteostasis, enhanced oxidative stress, and altered metabolism. We hypothesize
that these are linked through atypical thiol redox systems in DS cells. This increases vulnerability to
thiol-reactive xenobiotics through dysregulation of central carbon metabolism, modifying stem cell fate
decisions via altered regulation of Wnt/β-catenin signaling as a mechanism contributing to cognitive
dysfunction. Our prior results show that the environmental toxicant, maneb (MB), a neurotoxic dithiocarbamate
fungicide, impairs proteostasis, increases oxidative stress and displays greater toxicity in DS cells compared to
euploid controls. MB also modifies mitochondrial function, central carbon metabolism and our new preliminary
data show that DS cells display significant baseline alterations in the Wnt signaling pathway. Wnt signaling is a
vital cell signaling conduit critical for both stem cell maintenance and neurodevelopment. Therefore, elucidating
the environmental mechanisms impacting DS development, e.g. Wnt signaling and oxidative stress, will provide
a foundation to prioritize environmental chemical surveillance in DS neurodevelopment. Disruption of cellular
thiol redox systems, e.g. thiol redox proteome, is a key feature of oxidative stress. This mechanism is also critical
for embryonic development, where mitochondrially-derived reactive oxygen species (ROS) trigger stem cells to
differentiate. Thus, the approach detailed below will include thiol-reactive toxicants (TRT) as an innovative means
to study Gene-Environment interactions affecting neurodevelopment in a special population, DS. This proposal
involves three Specific Aims and makes use of a powerful library of euploid and trisomy 21 induced pluripotent
stem cells (iPSC) and directed differentiation protocols to investigate the role of thiol redox signaling in the effects
of TRT on stem cells derived from DS individuals, and how these exposures alter specific pathways (Wnt and
central carbon metabolism) during neurodevelopment. In Specific Aim 1 we will determine if trisomy 21-mediated
Wnt dysfunction is exacerbated by TRT exposure, resulting in aberrant iPSC differentiation. Western blotting,
qRT-PCR, chemical tools and single cell transcriptomics will be used to interrogate this aim. Specific Aim 2 is
designed to study the...

## Key facts

- **NIH application ID:** 10585469
- **Project number:** 2R01ES027593-06A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James R Roede
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,724,424
- **Award type:** 2
- **Project period:** 2017-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585469

## Citation

> US National Institutes of Health, RePORTER application 10585469, Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome. (2R01ES027593-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10585469. Licensed CC0.

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