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Published on: June 23, 2022
Nanoscale Discrimination between Toxic and Nontoxic Protein Misfolded Oligomers with Tip-Enhanced Raman Spectroscopy
Cristiano D'Andrea1, Antonino Foti2, Maximilien Cottat1
1IFAC-CNR, Institute of Applied Physics "Nello Carrara,", National Research Council, Via Madonna del Piano 10, I-50019, Sesto Fiorentino, Italy.
Abstract:
Highly toxic protein misfolded oligomers associated with neurological disorders such as Alzheimer's and Parkinson's diseases are nowadays considered primarily responsible for promoting synaptic failure and neuronal death. Unraveling the relationship between structure and neurotoxicity of protein oligomers appears pivotal in understanding the causes of the pathological process, as well as in designing novel diagnostic and therapeutic strategies tuned toward the earliest and presymptomatic stages of the disease. Here, it is benefited from tip-enhanced Raman spectroscopy (TERS) as a surface-sensitive tool with spatial resolution on the nanoscale, to inspect the spatial organization and surface character of individual protein oligomers from two samples formed by the same polypeptide sequence and different toxicity levels. TERS provides direct assignment of specific amino acid residues that are exposed to a large extent on the surface of toxic species and buried in nontoxic oligomers. These residues, thanks to their outward disposition, might represent structural factors driving the pathogenic behavior exhibited by protein misfolded oligomers, including affecting cell membrane integrity and specific signaling pathways in neurodegenerative conditions.
Insights
Toxic protein oligomers drive neurodegenerative diseases like Alzheimer's. Tip-enhanced Raman spectroscopy (TERS) identified specific surface amino acids on toxic oligomers, crucial for understanding and treating these conditions.
Area of Science:
- Neuroscience
- Biochemistry
- Spectroscopy
Background:
- Misfolded protein oligomers are implicated in neurodegenerative diseases, causing synaptic failure and neuronal death.
- Understanding the structure-toxicity relationship of these oligomers is key for early diagnosis and treatment.
- Current methods lack the resolution to analyze individual oligomer structures and their surface characteristics.
Purpose of the Study:
- To investigate the spatial organization and surface composition of individual protein oligomers.
- To correlate specific structural features with varying levels of neurotoxicity.
- To identify potential molecular targets for therapeutic intervention in neurodegenerative diseases.
Main Methods:
- Utilized tip-enhanced Raman spectroscopy (TERS), a nanoscale surface-sensitive technique.
- Analyzed two samples of the same polypeptide sequence exhibiting different toxicity levels.
- Performed high-resolution spatial analysis of individual protein oligomers.
Main Results:
- TERS enabled direct assignment of specific amino acid residues on the oligomer surfaces.
- Toxic oligomers showed a higher exposure of certain amino acid residues compared to non-toxic ones.
- These exposed residues are hypothesized to drive the pathogenic behavior of toxic oligomers.
Conclusions:
- Specific surface amino acid exposure correlates with protein oligomer neurotoxicity.
- TERS is a powerful tool for dissecting structure-toxicity relationships at the nanoscale.
- Identifying these surface residues offers potential for novel diagnostic and therapeutic strategies in neurodegenerative disorders.
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