A Central Role for Protein Aggregation in Neurodegenerative Disease; Mechanistic and Structural Studies of Human Stefins
Saša Jenko Kokalj, Veronika Stoka, Manca Kenig, Gregor Gunčar, Dušan Turk, and Eva Žerovnik*Abstract
Common cellular and molecular mechanisms underlie different neurodegenerative
diseases, from Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis to sporadic prion diseases. The molecular mechanisms include aberrant
protein folding and aggregation in the form of extracellular plaques or
intracellular inclusions. Deeper understanding of the detailed mechanism of
protein aggregation and cellular toxicity should lead to rational drug design
for this type of disease. Our studies of human stefin B, a model amyloidogenic
protein, will be reviewed. The studies range from establishing the mechanism,
imaging the fibrillar and prefibrillar species by transmission electron
microscopy (TEM) and atomic force microscopy (AFM), to structural studies of the
precursor oligomeric states.
Key words: amyloid-fibril, conformational disease, cystatins, domain-swapped dimer, protein folding