Abstract

Alzheimer's, Parkinson's, and Huntington's are neurodegenerative diseases currently incurable but uniquely defined by the deposition of neurotoxic proteins. They are intrinsically disordered proteins with very high causality for neurodegeneration. Tremendous advances have been realized in molecular pathogenesis with a view toward establishing causative genes and proteins. However, two important elements related to neurotoxic conformation and neuronal vulnerability remain unidentified. The prevailing hypothesis has been that pathogenic cascades are initiated by the conformational changes in the monomeric forms, and hence, these could be good targets for therapy. Single-molecule techniques, especially single-molecule force spectroscopy, have advanced the nanomechanics and conformational polymorphism of neurotoxic proteins. It has been shown that such polymorphism at the level of monomers is very strongly correlated with amyloidogenesis and neurotoxicity. Such polymorphism is, importantly, entirely absent in fibrillization-incompetent mutants but is enhanced by familial-disease mutations. There is also the case of pharmacological agents that inhibit β-conformational changes in monomers, dramatically reducing their polymorphism and associated neurotoxicity, indicating common molecular mechanisms for these diseases.

Advances in the manipulation and analysis of single molecules have dramatically enhanced our understanding of neurotoxic protein dynamics. Despite such advances, major questions remain about specific neurotoxic conformations and their role in selective neuronal degeneration. The solution to these challenges is crucial for the development of novel diagnostic, preventive, and therapeutic strategies against these devastating disorders, which carry significant social and clinical impact.

This abstract encapsulates the emerging potential of single-molecule studies to pave the way for innovative solutions in managing amyloidogenic neurodegenerative diseases.