Dataset Information

Quantifying Co-Oligomer Formation by ?-Synuclein.

ABSTRACT: Small oligomers of the protein ?-synuclein (?S) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, ?S can form co-aggregates with its mutational variants and with other proteins such as amyloid-? (A?) and tau, which are implicated in Alzheimer's disease. The processes of self-oligomerization and co-oligomerization of ?S are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques to measure the equilibrium populations of oligomers formed in vitro by mixtures of wild-type ?S with its mutational variants and with A?40, A?42, and a fragment of tau. Using a statistical mechanical model, we find that co-oligomer formation is generally more favorable than self-oligomer formation at equilibrium. Furthermore, self-oligomers more potently disrupt lipid membranes than do co-oligomers. However, this difference is sometimes outweighed by the greater formation propensity of co-oligomers when multiple proteins coexist. Our results suggest that co-oligomer formation may be important in PD and related neurodegenerative diseases.

SUBMITTER: Iljina M

PROVIDER: S-EPMC6262461 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Quantifying Co-Oligomer Formation by α-Synuclein.

Iljina Marija M Dear Alexander J AJ Garcia Gonzalo A GA De Suman S Tosatto Laura L Flagmeier Patrick P Whiten Daniel R DR Michaels Thomas C T TCT Frenkel Daan D Dobson Christopher M CM Knowles Tuomas P J TPJ Klenerman David D

ACS nano 20181029 11

Small oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, αS can form co-aggregates with its mutational variants and with other proteins such as amyloid-β (Aβ) and tau, which are implicated in Alzheimer's disease. The processes of self-oligomerization and co-oligomerization of αS are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques to measure the equilibrium populations of ol ...[more]

PMID: 30371053

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Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting the elderly population worldwide. In PD, the misfolding of α-synuclein (α-syn) results in the formation of inclusions referred to as Lewy bodies (LB) in midbrain neurons of the substantia nigra and other specific brain localizations, which is associated with neurodegeneration. There are no approved strategies to reduce the formation of LB in the neurons of patients with PD. Our drug discovery program focuses on the synthesis of urea and thiourea compounds coupled with aminoindole moieties to abrogate α-syn aggregation and to slow down the progression of PD. We synthesized several urea and thiourea analogues with a central 1,4-phenyl diurea/thiourea linkage and evaluated their effectiveness in reducing α-syn aggregation with a special focus on the selective inhibition of oligomer formation among other proteins. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), as well as M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. Our results identified compound 1 as the best compound in reducing α-syn fibril formation via ThT assays. The antioligomer formation of compound 1 was subsequently superseded by compound 2. Both compounds selectively curtailed the oligomer formation of α-syn but not tau 4R isoforms (0N4R, 2N4R) or p-tau (isoform 1N4R). Compounds 1 and 2 failed to abrogate tau 0N3R fibril formation by ThT and atomic force microscopy. Compound 2 was best at reducing the formation of recombinant α-syn fibrils by TEM. In contrast to compound 2, compound 1 reduced the formation of α-syn inclusions in M17D neuroblastoma cells in a dose-dependent manner. Compound 1 may provide molecular scaffolds for the optimization of symmetric molecules for its α-syn antiaggregation activity with potential therapeutic applications and development of small molecules in PD.

Dataset Information

Quantifying Co-Oligomer Formation by ?-Synuclein.

Publications

Quantifying Co-Oligomer Formation by α-Synuclein.

Similar Datasets

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