Background: The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown.
Methodology/principal Findings: In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects.
Conclusions/significance: Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851648 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009956 | PLOS |
Publication Analysis
Top Keywords
Similar Publications
In this study, heterozygous expression of a common Parkinson-associated GBA1 variant, the L444P mutation, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons were also shown to become more vulnerable to oxidative and nitrative stress after L444P expression. The latter paralleled neuronal formation of reactive oxygen species and led to a pronounced accumulation of nitrated α-synuclein.
View Article and Find Full Text PDFDimethyl labeling of N-terminal amines allows unambiguous identification of protein crosslinks.
Free Radic Biol Med
December 2024
Dept. of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:
Article Synopsis
- Protein crosslinks caused by oxidative stress are linked to diseases like atherosclerosis, Alzheimer's, and Parkinson's, but their specific nature and locations in proteins remain unclear.
- A new method utilizing "light" and "heavy" isotope-labeled reagents for efficient amine labeling of crosslinked peptides has shown improved identification and quantification over previous techniques.
- This approach has led to the successful identification of novel crosslinks in proteins like β-casein and α-synuclein, as well as effective mapping of disulfide bonds in serum albumin, highlighting its versatility for studying protein modifications.
Dysregulation of protein degradation and alteration of secretome in α-synuclein-exposed astrocytes: implications for dopaminergic neuronal dysfunction.
Cell Commun Signal
December 2024
Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, Karnataka, 560029, India.
Background: A key factor in the propagation of α-synuclein pathology is the compromised protein quality control system. Variations in membrane association and astrocytic uptake between different α-synuclein forms suggest differences in exocytosis or membrane cleavage, potentially impacting the secretome's influence on dopaminergic neurons. We aimed to understand differences in protein degradation mechanisms of astrocytes for both wild-type (WT) and mutant forms of α-synuclein, specifically during periods of reduced degradation efficiency.
View Article and Find Full Text PDFα-Synuclein pathology as a target in neurodegenerative diseases.
Nat Rev Neurol
January 2025
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
α-Synuclein misfolds into pathological forms that lead to various neurodegenerative diseases known collectively as α-synucleinopathies. In this Review, we provide a comprehensive overview of pivotal advances in α-synuclein research. We examine structural features and physiological functions of α-synuclein and summarize current insights into key post-translational modifications, such as nitration, phosphorylation, ubiquitination, sumoylation and truncation, considering their contributions to neurodegeneration.
View Article and Find Full Text PDFCircadian disruption promotes the neurotoxicity of oligomeric alpha-synuclein in mice.
NPJ Parkinsons Dis
September 2024
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China.
Circadian disruption often arises prior to the onset of typical motor deficits in patients with Parkinson's disease (PD). It remains unclear whether such a prevalent non-motor manifestation would contribute to the progression of PD. Diffusible oligomeric alpha-synuclein (O-αSyn) is perceived as the most toxic and rapid-transmitted species in the early stages of PD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!