# Controlling Bacterial Amyloid Formation and the Influence of Curli Subunits on Pathogenic Alpha-synuclein Aggregation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $304,335

## Abstract

Escherichia coli (E.coli) and other enteric bacteria are a major cause of human diseases. Biofilm formation
contributes greatly to bacterial persistence and antimicrobial resistance in the host. Many Enterobacteriaceae,
such as E. coli, produce functional amyloid fibers called curli as a major proteinaceous component of their
extracellular matrix. It is now clear that functional amyloids are widespread, with examples found throughout
cellular life. The curli system in E. coli provides a rich and high throughput genetic and biochemical toolbox for
the study of amyloid formation. The work has contributed to a curli assembly model where the main fiber
component CsgA and the minor subunit CsgB are secreted through the outer membrane-located CsgG. CsgB
attaches to the surface of the cell and templates the folding of CsgA into an amyloid fiber. CsgA subunits that
inappropriately polymerize in the periplasm are inhibited from amyloid accumulation via CsgC. The exquisitely-
controlled curli biogenesis system ensures that E. coli is not exposed to the potentially cytotoxic outcomes of
amyloid formation.
Uncontrolled or inappropriate amyloid formation results in several neurodegenerative diseases, including
Parkinson’s. The hallmark of Parkinson’s disease is the amyloid aggregation of alpha-synuclein, although it is
unknown how amyloid formation is initiated. Colonization of mice with curli amyloid producing bacteria results
in alpha-synuclein amyloid formation and Parkinson’s like symptoms. Furthermore, purified CsgA protein can
accelerate alpha-synuclein amyloid formation in vitro. Therefore, it is imperative to learn how E. coli controls
curli amyloid formation and how CsgA can accelerate alpha-synuclein amyloid formation. Interestingly, CsgC
from E. coli can inhibit CsgA and alpha-synuclein amyloid formation. Knowledge gained from the following
experiments will have implications for microbial pathogenesis, general protein folding, and amyloid biogenesis,
thus paving the way for new therapies that rationally target these critical biological processes. In Aim 1 The
mechanism and specificity of CsgC will be revealed, including how CsgC functions to inhibit CsgA and alpha-
synuclein polymerization at low stoichiometric ratios. In Aim 2 The relationship between the intrinsic ability of
CsgA to form amyloid and its ability to accelerate alpha-synuclein amyloid formation will be assessed. Finally,
in Aim 3 CsgA and CsgC-like proteins in the sequenced genomes of the human gut microbiota will be
identified and biochemically characterized. Together the successful completion of these aims will give an
overall understanding of the mechanism of amyloid inhibitory activity and the interactions between bacterial
amyloid formation and neurodegenerative diseases.

## Key facts

- **NIH application ID:** 9973388
- **Project number:** 2R01GM118651-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Matthew Richard Chapman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $304,335
- **Award type:** 2
- **Project period:** 2016-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973388

## Citation

> US National Institutes of Health, RePORTER application 9973388, Controlling Bacterial Amyloid Formation and the Influence of Curli Subunits on Pathogenic Alpha-synuclein Aggregation (2R01GM118651-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973388. Licensed CC0.

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