Cited by 148Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

Oxidative and nitrative alpha‐synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies

Open access
Schildknecht, Stefan, Gerding, Hanne R., Karreman, Christiaan, Drescher, Malte, Lashuel, Hilal A., Outeiro, Tiago F., Di Monte, Donato A., Leist, Marcel·2013·Journal of Neurochemistry

Abstract

Alpha‐synuclein (ASYN) is a major constituent of the typical protein aggregates observed in several neurodegenerative diseases that are collectively referred to as synucleinopathies. A causal involvement of ASYN in the initiation and progression of neurological diseases is suggested by observations indicating that single‐point (e.g., A30P, A53T) or multiplication mutations of the gene encoding for ASYN cause early onset forms of Parkinson's disease (PD). The relative regional specificity of ASYN pathology is still a riddle that cannot be simply explained by its expression pattern. Also, transgenic over‐expression of ASYN in mice does not recapitulate the typical dopaminergic neuronal death observed in PD. Thus, additional factors must contribute to ASYN‐related toxicity. For instance, synucleinopathies are usually associated with inflammation and elevated levels of oxidative stress in affected brain areas. In turn, these conditions favor oxidative modifications of ASYN. Among these modifications, nitration of tyrosine residues, formation of covalent ASYN dimers, as well as methionine sulfoxidations are prominent examples that are observed in post‐mortem PD brain sections. Oxidative modifications can affect ASYN aggregation, as well as its binding to biological membranes. This would affect neurotransmitter recycling, mitochondrial function and dynamics (fission/fusion),ASYN's degradation within a cell and, possibly, the transfer of modified ASYN to adjacent cells. Here, we propose a model on how covalent modifications of ASYN link energy stress, altered proteostasis, and oxidative stress, three major pathogenic processes involved in PD progression. Moreover, we hypothesize that ASYN may act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging.

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 · 10.1111/jnc.12226

Cites

238 of 238 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?

  • Neuronal presentation of α-synuclein fragments activates T cells that attack neurons, inducing autoimmune neurodegeneration.

    “Neuronal presentation of α-synuclein fragments activates T cells which then attack neurons, thereby inducing an autoimmune process of neurodegeneration (215).”

    From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [215]

    In ‘Influence of oxidative modifications on the toxicity of ASYN’ (p. 8), the paper says nitrated α-synuclein activates effector T cells that contribute to dopaminergic neuron degeneration. It does not say neurons present α-synuclein fragments to those T cells or that the T cells directly attack neurons; those steps in the claimed mechanism are unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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

1 retracted

Flagged first, then by citations

2 of the 240 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Authors
Schildknecht, S., Gerding, H. R., Karreman, C., Drescher, M., Lashuel, H. A., Outeiro, T. F., Di Monte, D. A., & Leist, M.
Affiliations
  • University of Konstanz (DE)
  • École Polytechnique Fédérale de Lausanne (CH)
  • Universitätsmedizin Göttingen (DE)
  • German Center for Neurodegenerative Diseases (DZNE) Bonn Germany
Corresponding author
Schildknecht, Stefan
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2013-03-19
Volume
125
Issue
4
Pages
491-511
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
OpenAlex
W2124819757
Cited by
148
References
240
Citations by year
2026: 4 · 2025: 9 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 12 · 2017: 18 · 2016: 17 · 2015: 12 · 2014: 13 · 2013: 4
FWCI
1.99
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • DZNE Pub (submittedVersion)
  • GRO (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Collaborative Research Center 969 “Chemical and Biological Principles of Cellular Proteostasis
  • Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein, synucleinopathies, Parkinson's disease, oxidative stress, nitration, tyrosine nitration, covalent dimers, protein aggregation, proteostasis, energy stress, mitochondrial dynamics, dopaminergic neurons, neuroinflammation, A30P mutation, A53T mutation
MeSH terms
Humans, Nerve Degeneration, Nitric Oxide, Parkinson Disease, Oxidative Stress, Peroxynitrous Acid, 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