Table 1.

Pathogenic protein seeding: Open questions

Mechanistic and theoretical issues:    What is the molecular structure of pathogenic proteins?    Why are synthetic and recombinant protein aggregates often poor seeds?    What co-factors influence the formation and activity of seeds?    Are there polystructural and polyfunctional strains of misfolded proteins?    What accounts for the selective vulnerability of neurons in the proteopathies?    How do protein assemblies move from cell to cell, and from region to region?    What are the mechanisms of intracellular vs. extracellular seeding?    Are some seeded aggregates protective, e.g. by binding toxic oligomers?    Is there cross-seeding between proteins, or between non-protein seeds and proteins?    Can exogenous corruptive seeds trigger non-prion neurodegenerative diseases?

Practical and clinical issues:    Can soluble protein seeds be targeted therapeutically or as disease biomarkers?    Is it necessary to impede the seeding cascade for cell transplantation or genetic therapies to be fully effective against neurodegenerative diseases?    Until the nature of non-prion seeds is better understood:  Should more rigorous decontamination of neurosurgical instruments be considered?  Should there by age limits for donating organs, tissues, extracts or fluids for medical purposes?  Should potential donors with known non-prion proteopathies be excluded from donating biological materials?  Are special precautions needed for professionals who handle biological materials from affected patients?  How can the hypothetical risk of exogenous induction of non-prion proteopathies best be assessed epidemiologically?