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Cited by 11Gut microbiota and healthParkinson's Disease Mechanisms and TreatmentsGastrointestinal motility and disorders

Alpha synuclein overexpression can drive microbiome dysbiosis in mice

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Sampson, Timothy R., Wallen, Zachary D, Won, Woong-Jai, Standaert, David G., Payami, Haydeh, Harms, Ashley S.·2025·Scientific Reports
DOI 10.1038/s41598-024-82139-7PMC PMC11787330

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Abstract

Growing evidence indicates that persons with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome before symptomatic onset and for the duration of the disease are currently lacking. PD is partially characterized by the accumulation of the protein α-synuclein (α-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, several experimental rodent and non-human primate models of α-syn overexpression recapitulate some of the hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease-relevant conditions. Here, we used a transgenic mouse strain, which overexpress wild-type human α-syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype-dependent bacterial taxa whose abundance becomes altered with age. We reveal that α-syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits diversity through age. Taxa that were most affected by genotype-age interaction were Lactobacillus and Bifidobacteria . In a mouse model, we showed direct link between alpha synuclein geneotype (hallmark of PD), a dysbiotic and low-diversity gut microbiome, and dysbiotic levels of Bifidobacteria and Lactobacillus (most robust features of PD microbiome). Given emerging data on the potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease.

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  • A recent study of transgenic α-synuclein overexpressing mice using gut microbial shotgun metagenomics highlighted that the onset of PD pathology is related to changes in gut bacterial taxa in an age- and genotype-dependent manner.

    “A recent study of transgenic α-synuclein overexpressing mice using gut microbial shotgun metagenomics highlighted that the onset of PD pathology is related to changes in gut bacterial taxa in an age- and genotype-dependent manner [88].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [88]

    The Abstract and Conclusion (pages unavailable) report shotgun metagenomics in α-synuclein-overexpressing mice and bacterial taxa that changed with age and genotype. However, the Discussion (page unavailable) says the study could not correlate inflammatory markers or α-synuclein overexpression with microbiome changes. It therefore supports changes in a mouse model of PD-related pathology, but not a measured relationship between the onset of PD pathology and those changes. (LLM, conf=0.87)

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  1. [1]Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276 (5321), 2045–2047 (1997). 9197268 · DOI · Paper page
  2. [2]Maraganore, D. M. et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296 (6), 661–670 (2006). 16896109 · DOI
  3. [3]Ross, O. A. et al. Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann. Neurol. 63 (6), 743–750 (2008). 18571778 PMC3850281 · DOI
  4. [4]Harms, A. S. et al. Inflammation in experimental models of alpha-synucleinopathies. Mov. Disord 36 (1), 37–49 (2021). 33009855 PMC8115204 · DOI
  5. [5]Volpicelli-Daley, L. A. et al. How can rAAV-alpha-synuclein and the fibril alpha-synuclein models advance our understanding of Parkinson’s disease? J. Neurochem 139 (Suppl 1), 131–155 (2016). 27018978 PMC5040622 · DOI
  6. [6]Braak, H. et al. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm (Vienna) 110 (5), 517–536 (2003). 12721813 · DOI · Paper page
  7. [9]Challis, C. et al. Gut-seeded alpha-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat. Neurosci. 23 (3), 327–336 (2020). 32066981 PMC7065967 · DOI · Paper page
  8. [10]Kim, S. et al. Transneuronal Propagation of pathologic alpha-synuclein from the gut to the Brain models Parkinson’s Disease. Neuron 103 (4), 627–641e7 (2019). 31255487 PMC6706297 · DOI · Paper page
  9. [12]Arotcarena, M. L. et al. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain 143 (5), 1462–1475 (2020). 32380543 · DOI · Paper page
  10. [13]Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18 (12), 1091–1102 (2019). 31701892 PMC8422160 · DOI · Paper page
  11. [14]Wallen, Z. D. et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nat. Commun. 13 (1), 6958 (2022). 36376318 PMC9663292 · DOI · Paper page
  12. [16]Romano, S. et al. Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis. 7 (1), 27 (2021). 33692356 PMC7946946 · DOI · Paper page
  13. [17]Toh, T. S. et al. Gut microbiome in Parkinson’s disease: new insights from meta-analysis. Parkinsonism Relat. Disord 94, 1–9 (2022). 34844021 · DOI
  14. [18]Boktor, J. C. et al. Integrated Multi-cohort Analysis of the Parkinson’s Disease Gut Metagenome. Mov. Disord 38 (3), 399–409 (2023). 36691982 · DOI
  15. [19]Bhattarai, Y. et al. Role of gut microbiota in regulating gastrointestinal dysfunction and motor symptoms in a mouse model of Parkinson’s disease. Gut Microbes 13 (1), 1866974 (2021). 33459114 PMC7833732 · DOI · Paper page
  16. [22]Pu, Y. et al. Antibiotic-induced microbiome depletion protects against MPTP-induced dopaminergic neurotoxicity in the brain. Aging (Albany NY) 11 (17), 6915–6929 (2019). 31479418 PMC6756889 · DOI · Paper page
  17. [23]Sampson, T. R. et al. Gut microbiota regulate Motor deficits and neuroinflammation in a model of Parkinson’s Disease. Cell 167 (6), 1469–1480e12 (2016). 27912057 PMC5718049 · DOI · Paper page
  18. [24]Rockenstein, E. et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res. 68 (5), 568–578 (2002). 12111846 · DOI · Paper page
  19. [26]Ewels, P. et al. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32 (19), 3047–3048 (2016). 27312411 PMC5039924 · DOI · Paper page
  20. [28]Anderson, M. J. A new method for non-parametric multivariate analysis of variance. Austral Ecol. 26 (1), 32–46 (2001).
  21. [30]Lin, H. & Peddada, S. D. Analysis of compositions of microbiomes with bias correction. Nat. Commun. 11 (1), 3514 (2020). 32665548 PMC7360769 · DOI
  22. [31]Hochberg, Y. & Benjamini, Y. More powerful procedures for multiple significance testing. Stat. Med. 9 (7), 811–818 (1990). 2218183 · DOI · Paper page
  23. [32]Watson, M. B. et al. Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp. Neurol. 237 (2), 318–334 (2012). 22750327 PMC3443323 · DOI
  24. [33]Wang, L. et al. Abnormal colonic motility in mice overexpressing human wild-type alpha-synuclein. Neuroreport 19 (8), 873–876 (2008). 18463504 PMC3108489 · DOI
  25. [34]Wang, L. et al. Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol Motil. 24 (9), e425–e436 (2012). 22779732 PMC3712640 · DOI
  26. [36]Houser, M. C. et al. Stool Immune profiles Evince gastrointestinal inflammation in Parkinson’s Disease. Mov. Disord. 33 (5), 793–804 (2018). 29572994 PMC5992021 · DOI
  27. [37]Radisavljevic, N. et al. Effects of Gut Microbiota alterations on motor, gastrointestinal, and behavioral phenotype in a mouse model of Parkinson’s Disease. J. Parkinsons Dis. 12 (5), 1479–1495 (2022). 35599496 · DOI
  28. [38]Wallen, Z. D. et al. Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens. NPJ Parkinsons Dis. 6, 11 (2020). 32566740 PMC7293233 · DOI · Paper page
  29. [39]Sun, M. F. et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-alpha signaling pathway. Brain Behav. Immun. 70, 48–60 (2018). 29471030 · DOI · Paper page
  30. [40]Richter, F. et al. A mouse model to test Novel therapeutics for Parkinson’s Disease: an update on the Thy1-aSyn (line 61) mice. Neurotherapeutics 20 (1), 97–116 (2023). 36715870 PMC10119371 · DOI

Cited by

Sorted by citations

Authors
Sampson, T. R., Wallen, Z. D., Won, W.-J., Standaert, D. G., Payami, H., & Harms, A. S.
Affiliations
  • Emory University (US)
  • University of Alabama at Birmingham (US)
Corresponding author
  • Payami, Haydeh
  • Harms, Ashley S.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2025-02-01
Volume
15
Issue
1
Pages
4014-4014
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-024-82139-7
PMC
PMC11787330
OpenAlex
W4407063464
Cited by
11
References
10
Citations by year
2026: 5 · 2025: 6
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Aligning Science Across Parkinson’s (ASAP-020527, ASAP-000375)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
alpha-synuclein, Parkinson's disease, gut microbiota, dysbiosis, alpha-synuclein overexpression, transgenic mouse model, aging, bacterial diversity, Lactobacillus, Bifidobacterium, gut-brain axis
MeSH terms
Gastrointestinal Microbiome, Aging, Animals, Disease Models, Animal, Humans, Male, Mice, Transgenic, Parkinson Disease, Mice, alpha-Synuclein, Dysbiosis

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