Oxidative and nitrative alpha‐synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies
Open accessAbstract
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.
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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)
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- 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
- bronze
- doi.org
- 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
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