As you know " Change in Aggregating alpha-Synuclein Levels" is one of the outcome measures in the both 201 and 202 study and also in the primate study. But we have so far got no results what happens to this very critical molecule of alpha-synuclein when patients are on ATH434 medication.

Now Prof. Masters and 2 groups of Sidney universities have published a paper to understand this seed amplification of alpha synuclein which is critical in MSA and PD. Most likely these scientists can help Stamler to get how ATH434 works on this molecule aggrecates. But may take time, if they have not started already now.

The paper is here: https://pubs.acs.org/doi/10.1021/acschemneuro.4c00185

Abstract below:

ACS Chem Neurosci

. 2024 Aug 28.

doi: 10.1021/acschemneuro.4c00185. Online ahead of print.

Single-Molecule Fingerprinting Reveals Different Growth Mechanisms in Seed Amplification Assays for Different Polymorphs of α-Synuclein Fibrils

Derrick Lau ¹, Yuan Tang ², Vijaya Kenche ³, Thomas Copie ¹, Daryan Kempe ¹, Eve Jary ¹, Noah J Graves ¹, Maté Biro ¹, Colin L Masters ³, Nicolas Dzamko ², Yann Gambin ¹, Emma Sierecki ¹

Affiliations Expand

• PMID: 39197832

DOI: 10.1021/acschemneuro.4c00185

Abstract

α-Synuclein (αSyn) aggregates, detected in the biofluids of patients with Parkinson's disease (PD), have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinson's disease and turns the presence of αSyn aggregates into a biomarker of the disease. It has become evident that αSyn can form fibrils with slightly different structures, called "strains" or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here, we compared the properties of two well-described αSyn polymorphs. Using single-molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences in reactivity observed in in vitro seed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in the apparent rate of growth can be generated by a surprisingly low number of secondary nucleation "points" (1 every 2000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end product.