Gut Microbiome-Modified Polyphenolic Compounds Inhibit α-Synuclein Seeding and Spreading in α-Synucleinopathies

Tritia R. Yamasaki; Kenjiro Ono; Lap Ho; Giulio M. Pasinetti

doi:10.3389/fnins.2020.00398

Gut Microbiome-Modified Polyphenolic Compounds Inhibit α-Synuclein Seeding and Spreading in α-Synucleinopathies

Tritia R. Yamasaki
, Kenjiro Ono
, Lap Ho
, Giulio M. Pasinetti

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.

Original language	English
Article number	398
Journal	Frontiers in Neuroscience
Volume	14
DOIs	https://doi.org/10.3389/fnins.2020.00398
State	Published - May 4 2020

Bibliographical note

Publisher Copyright:
© Copyright © 2020 Yamasaki, Ono, Ho and Pasinetti.

Funding

This study was supported by the Movement Disorder Bank at Washington University in St. Louis (NIH grant NS075321), American Parkinson Disease Association (APDA), Greater St. Louis Chapter of the APDA, and the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund). The study was approved by the ethical committee at the Washington University at St. Louis for use of post mortem de-identified, non-traceable data to any subjects. This study was also supported in part by the NIH-NCCIH and the ODS to GP. GP holds a Senior VA Career Scientist Award. TY was supported in part by a grant from the NCATS CCTS KL2 TR000116 at University of Kentucky. We acknowledge that the contents of this study do not represent the views of the NCCIH, the ODS, the NIH, the U.S. Department of Veterans Affairs, or the United States Government. Funding. This study was supported by the Movement Disorder Bank at Washington University in St. Louis (NIH grant NS075321), American Parkinson Disease Association (APDA), Greater St. Louis Chapter of the APDA, and the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund). The study was approved by the ethical committee at the Washington University at St. Louis for use of post mortem de-identified, non-traceable data to any subjects. This study was also supported in part by the NIH-NCCIH and the ODS to GP. GP holds a Senior VA Career Scientist Award. TY was supported in part by a grant from the NCATS CCTS KL2 TR000116 at University of Kentucky. We acknowledge that the contents of this study do not represent the views of the NCCIH, the ODS, the NIH, the U.S. Department of Veterans Affairs, or the United States Government.

Funders	Funder number
Foundation for Barnes-Jewish Hospital
NCATS CCTS	KL2 TR000116
NIH NCCIH
National Institutes of Health (NIH)	NS075321
Office of Dietary Supplements
U.S. Department of Veterans Affairs
American Parkinson Disease Association
Washington University in St. Louis
University of Kentucky
International Parkinson and Movement Disorder Society
National Center for Complementary and Integrative Health

Keywords

Parkinson’s disease
aggregation
microbiome
multiple system atrophy
polyphenol
α-synuclein

ASJC Scopus subject areas

General Neuroscience

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10.3389/fnins.2020.00398

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title = "Gut Microbiome-Modified Polyphenolic Compounds Inhibit α-Synuclein Seeding and Spreading in α-Synucleinopathies",

abstract = "Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson{\textquoteright}s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.",

keywords = "Parkinson{\textquoteright}s disease, aggregation, microbiome, multiple system atrophy, polyphenol, α-synuclein",

author = "Yamasaki, \{Tritia R.\} and Kenjiro Ono and Lap Ho and Pasinetti, \{Giulio M.\}",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Yamasaki, Ono, Ho and Pasinetti.",

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doi = "10.3389/fnins.2020.00398",

language = "English",

volume = "14",

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AU - Yamasaki, Tritia R.

AU - Ono, Kenjiro

AU - Ho, Lap

AU - Pasinetti, Giulio M.

PY - 2020/5/4

Y1 - 2020/5/4

N2 - Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.

AB - Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.

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KW - aggregation

KW - microbiome

KW - multiple system atrophy

KW - polyphenol

KW - α-synuclein

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UR - https://www.scopus.com/pages/publications/85085110129#tab=citedBy

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DO - 10.3389/fnins.2020.00398

M3 - Article

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ER -

Gut Microbiome-Modified Polyphenolic Compounds Inhibit α-Synuclein Seeding and Spreading in α-Synucleinopathies

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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