# Single-cell genetic analysis of the pathogenic role of neuronal genomic instability in environmental toxicant exposure

> **NIH NIH R21** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2020 · $219,000

## Abstract

Project Summary/Abstract
The majority of all Parkinson’s disease (PD) cases have no identifiable inheritance and occur in a sporadic form.
Epidemiologic studies have found an increased risk of PD associated with exposure to environmental, while the
reduced risk of PD associated with coffee consumption. The recent single-neuron sequencing studies offer direct
evidence there is an age-dependent increase of somatic brain mutations, suggesting adult terminally
differentiated neurons can acquire somatic mutations, possibly precipitated by environmental factors. Given the
plethora of correlational evidence describing pathological conditions in which levels of DNA damage/response
and mutations were identified, the most critical question is the extent to which the significance of such DNA
instability has relevance for the pathogenesis of neurodegeneration. One clue comes from a protective
environmental factor of PD, caffeine. Its antiparkinsonian effects have been attributed to the potent inhibition of
the Ataxia-Telangiectasia Mutated (ATM) pathway. ATM is the key orchestrator of oxidative stress and DNA
damage response (DDR). Robust DDR has been closely connected to multiple neurodegenerative disorders.
We hypothesize that the exposure to PD associated environmental toxicants compromises genomic stability to
abnormally activate the DNA damage response (converging on ATM activation), which plays a central
pathogenic role to lead to the final demise of neurodegeneration. Attenuating abnormally activated ATM signaling
is neuroprotective. Employing our newly developed Mosaicism with Repeat Frameshift (MORF) strategy, we
demonstrated the instability of a hypermutable repeat sequence (accounting for 3% of human genome) could be
harnessed for sparse and stochastic visualize neurodegeneration and genomic instability in aging, stroke, and
neurodegeneration. In aim 1, we will develop an AAV mediated quantitative ratiometric sensor of genomic
instability that integrates the varying lengths of mononucleotide repeats, incompatible LoxP sites, and
membrane-tethered multi-color fluorescence proteins. We will use both AAV and transgenic MORF strategy to
track single-neuron with DNA instability after environmental toxicant exposure to determine the pathologic
consequence. In aim 2, we will determine if the genetic reduction of DNA damage response in somatic cells with
DNA instability can rescue DA neuron degeneration. Our project will develop a novel genetic sensor and actuator
to study somatic brain mosaicism. The results will reveal the pathogenic significance of environment-driven
neuronal genomic instability and the crucial role of the DDR pathway, thus transforming the current paradigm of
the pathogenic role of environmental toxicant exposure in sporadic PD.
1

## Key facts

- **NIH application ID:** 10057617
- **Project number:** 1R21ES031211-01A1
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Xiaohong Lu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $219,000
- **Award type:** 1
- **Project period:** 2020-09-22 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057617

## Citation

> US National Institutes of Health, RePORTER application 10057617, Single-cell genetic analysis of the pathogenic role of neuronal genomic instability in environmental toxicant exposure (1R21ES031211-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10057617. Licensed CC0.

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