# The contribution of the vermiform appendix to Parkinson's disease

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $446,500

## Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by motor and non-motor
symptoms. The hallmark pathology of PD in the brain is the presence of alpha-synuclein (α-syn) aggregates,
along with the loss of dopaminergic neurons in the substantia nigra. The brain α-syn pathology is thought to
start in the gastrointestinal (GI) tract, since both GI dysfunction and the presence of α-syn aggregates in the GI
tract usually precede motor symptoms by many years. In addition, experimental models show that α-syn
aggregates can reach the brain from the gut via the vagal nerve. To understand GI tract contributions to PD,
we performed a study that identified the human appendix as a key GI tissue that impacts the risk for PD. This
study demonstrated that α-syn aggregates are abundant in the appendix and that removal of the appendix was
associated with a reduced risk of PD. It also showed that the appendix contains aberrant truncated forms of α-syn, analogous to those in the PD brain, and that these were more abundant in the appendix of PD patients
than in healthy individuals. This innovative work provides the basis for a unique opportunity to understand how
the appendix contributes to PD.
The proposed study will determine how the appendix, and the α-syn aggregates within, can impact the
development of PD. Specifically, this project aims to establish: 1) what gene regulatory changes are prominent
in the PD appendix compared to that of healthy controls; 2) the specific truncated forms of α-syn enriched in
the PD appendix and their capacity to seed further aggregation; 3) the consequences of initiating α-syn
pathology in the appendix on the subsequent development of PD-like pathology in the brain, in vivo. This study
will generate detailed genome-wide maps of epigenetic abnormalities in the PD appendix – a resource for
understanding gene regulatory and biological pathway changes in the PD GI tract. Profiling the epigenetic
mark DNA methylation will be accompanied by an integrative network analysis with transcriptomic data to
determine key genes dysregulated in the PD appendix. Next, the identification of the truncated α-syn
proteoforms elevated in the PD appendix, will be carried out using top-down mass spectrometry, the gold-standard for intact protein identification. Furthermore, seeding activity for pathogenic α-syn in the appendix of
PD cases, will be determined and compared to controls, using powerful biochemical assays. Finally, the
capacity for α-syn pathology triggered in the mouse cecal patch – aka the appendix – to lead to the
development of PD-like neuropathology in the brain, will be determined. We will also determine if intestinal
inflammation in combination with α-syn pathology in the cecal patch augments brain pathology relevant to PD.
Together, this study will provide new insights on the mechanisms underlying α-syn abnormalities in the PD gut
and its capacity to induce brain neuropathology. Moreover, this work can help...

## Key facts

- **NIH application ID:** 10052082
- **Project number:** 1R01NS114409-01A1
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Patrik Brundin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,500
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052082

## Citation

> US National Institutes of Health, RePORTER application 10052082, The contribution of the vermiform appendix to Parkinson's disease (1R01NS114409-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052082. Licensed CC0.

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