Towards Inhibition of α-Synuclein Aggregation

A small number of the thousands of different proteins in the body are capable of misfolding in ways that encourage other molecules of the same protein to misfold in the same way. These misfolded proteins spread, multiply, and form solid aggregates. The surrounding halo of altered biochemistry that attends these aggregates is harmful to cells, leading to dysfunction, inflammation, and even cell death. Many neurodegenerative conditions involve protein aggregation, of amyloid-β, α-synuclein, and tau, among others. Aggregation of misfolded transthyretin, meanwhile, contributes to cardiovascular disease and other conditions.

The dominant therapeutic approach for most of the protein aggregates in the brain is clearance via immunotherapy. For transthyretin, the research and development community has focused on use of small molecules that inhibit the misfolding and aggregation process, allowing cellular quality control mechanisms to catch up with the task of degrading aggregates. This inhibition approach could be applied to other protein aggregates as well, as illustrated by today's research materials focused on α-synuclein.

"Anti-tangle" molecule could aid search for new dementia treatments

Alpha-synuclein, a protein found in brain cells, is commonly associated with neurodegenerative diseases such as Parkinson's, a debilitating neurological disorder affecting millions worldwide. In healthy individuals, alpha-synuclein interacts with cell membranes where it plays a role in how brain cells (neurons) communicate with each other, but as a person ages, the 3D shape of the protein can malform, or "misfold", causing it to start sticking together to form toxic clumps in the brain. Over time these clumps continue to stack, forming fibres that can interfere with the protein's normal role, eventually killing brain cells, contributing to the development of Parkinson's and related dementia diseases.

A team of scientists took a protein fragment, or peptide, from one end of the alpha-synuclein protein strand and mixed it with samples of the full-length alpha-synuclein protein. They found that the fragment prevented misfolding in vitro, by stabilising its normal structure to prevent it from tangling, forming clumps and disrupting the cell membrane. This research opens up new avenues for therapeutic development, potentially in the future leading to drugs that can target and disrupt alpha-synuclein misfolding, ultimately preventing or slowing down the progression of diseases like Parkinson's.

An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation

Misfolding and aggregation of alpha-synuclein (αS) into toxic conformations is involved in numerous neurodegenerative diseases. In Parkinson's disease (PD), this occurs within dopaminergic neurons, causing cell death and disease symptoms. During αS aggregation, many protein-protein interactions (PPIs) form over broad and flat protein surfaces, limiting potential for small-molecule intervention. Peptides, however, harbor great therapeutic promise since they can selectively engage with and modulate the large surface areas involved yet are small enough to function as druggable agents if suitably structured.

Here, we explore the first 25 residues of αS (αS1-25) as a template for peptide-based αS aggregation antagonists. We report that αS1-25 inhibits lipid-induced αS aggregation in a dose-dependent manner. αS1-25 functions by binding to lipids to prevent αS binding, with both αS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.

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