A single-molecule study reveals that neurotoxic proteins share common structural features that may trigger neurodegeneration, thus identifying new targets for therapy and diagnosis.
Amyloidogenic neurodegenerative diseases are incurable conditions with high social impact that are typically caused by specific, largely disordered proteins. However, the underlying molecular mechanism remains elusive to established techniques. A favored hypothesis postulates that a critical conformational change in the monomer (an ideal therapeutic target) in these “neurotoxic proteins” triggers the pathogenic cascade. We use force spectroscopy and a novel methodology for unequivocal single-molecule identification to demonstrate a rich conformational polymorphism in the monomer of four representative neurotoxic proteins. This polymorphism strongly correlates with amyloidogenesis and neurotoxicity: it is absent in a fibrillization-incompetent mutant, favored by familial-disease mutations and diminished by a surprisingly promiscuous inhibitor of the critical monomeric β-conformational change, neurotoxicity, and neurodegeneration. Hence, we postulate that specific mechanostable conformers are the cause of these diseases, representing important new early-diagnostic and therapeutic targets. The demonstrated ability to inhibit the conformational heterogeneity of these proteins by a single pharmacological agent reveals common features in the monomer and suggests a common pathway to diagnose, prevent, halt, or reverse multiple neurodegenerative diseases.
Neurodegenerative diseases like Alzheimer's or Parkinson's are currently incurable. They are caused by different proteins that, under certain circumstances, aggregate and become toxic as we grow older, but the molecular events underlying this process remain unclear. The lack of a well-defined structure, and the tendency of these “neurotoxic proteins” to aggregate make them difficult to study using conventional techniques. Here, we use an established single-molecule manipulation technique combined with a new protein-engineering strategy to show that all these proteins can adopt a rich collection of structures (conformers) that includes a high proportion of mechanostable conformers, which are associated with toxicity and disease. We also find that a known drug can block the formation of these mechanostable structures in different neurotoxic proteins. We suggest that the most mechanostable conformers, or their precursors, may trigger the pathogenic cascade that results in toxicity. We thus propose that these mechanostable structures are ideal targets for early diagnosis, prevention, and treatment of these fatal diseases.