Protein Misfolding and Disease

Although protein folding is normally an extraordinary robust process it sometimes goes wrong. In several severe diseases, such misfolding events lead to neural degeneration accompanied by in vivo deposition of protein aggregates or amyloid fibrils. However, it is not the visible protein deposits that seem to be the prime cause of the neurotoxicity but their precursors or other misfolded/partly folded species accumulating in connection to the aggregation process. To identify these toxic components, we work with the motor neuron disease ALS that is linked to misfolding of the radical scavenger superoxide dismutase (SOD1). As model for protein disease this system presents several advantages. The number of SOD1 mutations known to trigger ALS (>130) is larger than for any other neurodegenerative disorder and more than 50 of these mutations are associated with characteristic and variable clinical features. This comprehensive set of structural and clinical data presents a unique reference for elucidation of the factors triggering toxic gain of function at molecular/biophysical level. Also, SOD1 displays the archetypical properties of globular proteins allowing detailed biophysical and structural analysis of mutational perturbations.