Cited by 282Alzheimer's disease research and treatmentsParkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

Open access
Tsigelny, Igor F., Crews, Leslie, Desplats, Paula, Shaked, Gideon M., Sharikov, Yuriy, Mizuno, Hideya, Spencer, Brian, Rockenstein, Edward +4 more·2008·PLoS ONE

Abstract

BACKGROUND: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta) oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Abeta promotes alpha-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and Abeta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Abeta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Abeta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and Abeta dimers that dock on the membrane incorporated additional alpha-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Abeta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with Abeta displayed increased current amplitudes and calcium influx consistent with the formation of cation channels. CONCLUSION/SIGNIFICANCE: These results support the contention that Abeta directly interacts with alpha-syn and stabilized the formation of hybrid nanopores that alter neuronal activity and might contribute to the mechanisms of neurodegeneration in AD and PD. The broader implications of such hybrid interactions might be important to the pathogenesis of other disorders of protein misfolding.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0003135This paper is marked retracted.

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • αSyn monomers, dimers, trimers and pentamers bind to monomeric amyloid-β in post-mortem samples from Alzheimer's disease and dementia with Lewy bodies brains.

    “Co-immunoprecipitation experiments have shown that αSyn monomers, dimers, trimers and pentamers bind to monomeric Aβ in post-mortem samples from AD and DLB brains [67].”

    From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [67]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 115 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. [34]McKeith I Galasko D Kosaka K Perry E Dickson D 1996 Clinical and pathological diagnosis of dementia with Lewy bodies (DLB): Report of the CDLB International Workshop. Neurology 47 1113 1124 8909416

Cited by

Sorted by citations

Authors
Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., Platoshyn, O., Yuan, J. X.-J., & Masliah, E.
Affiliations
  • San Diego Supercomputer Center (US)
  • University of California San Diego (US)
Corresponding author
Masliah, Eliezer
Venue
PLoS ONE
Published
2008-09-04
Volume
3
Issue
9
Pages
e3135
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2065878937
Cited by
281
References
115
Citations by year
2026: 3 · 2025: 12 · 2024: 14 · 2023: 14 · 2022: 13 · 2021: 18 · 2020: 25 · 2019: 20 · 2018: 18 · 2017: 22 · 2016: 16 · 2015: 18 · 2014: 14 · 2013: 9 · 2012: 21
FWCI
9.93
Type
journal article
Language
en
Status
Retracted
Open access
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Energy
  • National Institutes of Health (AG‐18440)
  • National Institute on Aging (R37AG018440, R01AG018440, AG 18440)
  • National Heart, Lung, and Blood Institute (R01HL066012, HL066012)
  • Argonne National Laboratory
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, Parkinson's disease, amyloid-beta, alpha-synuclein, protein-protein interaction, protein misfolding, Lewy body disease, nanopores, cation channels, calcium influx, protein aggregation, transgenic mice
MeSH terms
Alzheimer Disease, Animals, Brain, Calcium, Computer Simulation, Electrophysiology, Humans, Mice, Transgenic, Parkinson Disease, Protein Denaturation, Protein Structure, Tertiary, Protein Folding, Lewy Body Disease, Mice, alpha-Synuclein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review