Objective: To differentiate and characterize alpha-synuclein strains and sub-strains associated with synucleinopathies.

Background: Synucleinopathies are a diverse group of neurodegenerative diseases characterized by misfolding aggregation and accumulation of misfolded alpha-synuclein (αSyn) in neurons or glial cells, which include Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB).  Clinically, it is very challenging to differentiate particularly PD from MSA, especially at the early stage of the disease. Accumulating evidence suggests that αSyn aggregates associated with different synucleinopathies adopt distinct conformational strains. Our results also suggest the existence of distinct aSyn strains with the same disease (here called sub-strains to avoid confusion). aSyn strains and sub-strains faithfully self-propagate and spread between cells. We propose that discrimination of these conformational αSyn strains and sub-strains hold promise for differential diagnosis and understanding the relationship between structures of αSyn strains and sub-strains and their pathologic functions

Method: We used protein misfolding cyclic amplification (PMCA) assay to detect αSyn oligomers in cerebrospinal fluid (CSF) referred to as αSyn-PMCA, which exploits the functional properties of these oligomers to seed soluble monomers used as substrates thus facilitating their detection [1]. Further, we used a combination of biochemical, structural and biological methods to characterize the amplified products of αSyn-PMCA.

Results: αSyn-PMCA assay could readily discriminate between CSF samples from PD and MSA patients with high sensitivity [2]. Moreover, the characteristics of amplified aggregates from the CSF of PD patients differed from aggregates amplified from CSF of MSA patients [2]. We also found that the properties of aggregates that were amplified from CSF samples were similar to those amplified from the brain samples. Most importantly, we were able to subgroup PD and MSA patients based on αSyn-PMCA parameters and characteristics of amplified aggregates from CSF samples.

Conclusion: The findings obtained here will not only help to understand the relationship between the structure of αSyn strains and sub-strains and their pathologic function but may also help to discriminate diverse synucleinopathies, which will help in patients’ stratification, target enrollment for clinical trial and personalized treatment.

References: [1]. Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C, Mollenhauer B, Soto C. Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid. JAMA Neurology. 2017 Feb 1;74(2):163-172. doi: 10.1001/jamaneurol.2016.4547. [2]. Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KPR, Low PA, Soto C. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature. 2020 Feb; 578(7794):273-277. doi: 10.1038/s41586-020-1984-7. Epub 2020 Feb 5.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/discrimination-of-alpha-synuclein-strains-and-sub-strains-in-synucleinopathies/