# Towards a comprehensive understanding of the neurotoxic spread of α-synuclein from gut to brain in Parkinson's disease

> **NIH NIH DP2** · AUGUSTA UNIVERSITY · 2024 · $1,386,000

## Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disorder for which disease-modifying therapies
do not currently exist and the underlying mechanisms remain incompletely understood. PD is characterized by
the loss of dopaminergic and other neuronal cell types, and the formation of pathological Lewy body inclusions
containing aggregated α-synuclein protein. Increasing evidence suggests that α-synuclein aggregation may
originate in neurons innervating the gastrointestinal tract, and spread to the central nervous system in a prion-
like manner. While rodent models have demonstrated that gut-to-brain spreading of α-synuclein can occur and
results in neurodegeneration and behavioral decline, major challenges associated with the low-throughput nature
of these model systems have hindered progress in the field. To address these issues and significantly accelerate
the rate of discovery of novel disease mechanisms, we propose to generate new gut-to-brain α-synuclein
transmission models in C. elegans, a rapidly aging and highly genetically tractable model organism amenable to
large-scale investigations. We will construct and integrate brain-wide maps of spreading α-synuclein pathology
and neurodegeneration, revealing vulnerable and resilient neuronal cell types in the face of α-synuclein insult
from the gut. To decipher cell type-specific mechanisms that underlie these differential susceptibilities, we will
use a combination of high-throughput screening and single cell RNA-sequencing. Known and predicted cell
surface proteins will be systematically tested for a potential role as novel α-synuclein receptors, facilitating the
toxic invasion of α-synuclein into neurons. Nervous system-wide, single cell transcriptional analyses will provide
powerful insights into both protective and detrimental factors responsible for the fate of neurons in the path of
gut-to-brain α-synuclein transmission. Collectively, this work will constitute the most comprehensive investigation
to date of the mechanisms regulating α-synuclein neurotoxic propagation from the gut, linking cellular- and
molecular-level events at unprecedented resolution, with neuronal degeneration and whole-organism behavioral
dysfunction. Given the accessibility of the human gut to pharmacological and dietary interventions, the results of
this study may inform early therapeutic strategies that hold great promise to halt or even prevent PD progression.

## Key facts

- **NIH application ID:** 10910663
- **Project number:** 1DP2NS142716-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Danielle Emille Mor
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,386,000
- **Award type:** 1
- **Project period:** 2024-09-17 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910663

## Citation

> US National Institutes of Health, RePORTER application 10910663, Towards a comprehensive understanding of the neurotoxic spread of α-synuclein from gut to brain in Parkinson's disease (1DP2NS142716-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10910663. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*