Functional and pathological amyloid in humans

Under the right conditions, most proteins can oligomerize to form a fibrillar, cross beta-sheet quaternary structure called amyloid. Amyloid is associated with a number of degenerative diseases, including Parkinson disease, where its formation is correlated with tissue damage. Thus, amyloid has been considered toxic and was not thought to play a useful role in biology. Since 2000, a number of functional protein fibers in bacteria, yeast, insects, fungi and even invertebrates have been shown to be amyloid, suggesting that amyloid might be an evolutionarily conserved functional protein structure. We have demonstrated that fibers derived from the protein Pmel17 are the first human functional amyloid, serving as a template for the synthesis of the important tyrosine-based pigment melanin. The highly regulated nature of Pmel17 amyloid formation illustrates several key adaptations enabling the use of amyloid for function. On the other hand, the normal function and regulation of disease-associated amyloidogenic proteins can be related to their pathology. Thus, we sought to understand the normal function of the amyloidogenic alpha-synuclein protein, whose aggregation is associated with Parkinson disease. alpha-Synuclein is a presynaptic protein thought to be involved in neurotransmitter vesicle trafficking---we have discovered that it functions in synaptic vesicle tethering and fusion. alpha-Synuclein interaction with tethering proteins such as p115 suggests a mechanism of alpha-synuclein aggregate-mediated neurotoxicity, namely sequestration of vital trafficking proteins by alpha-synuclein aggregates and subsequent neuronal dysfunction. Our studies reveal that under tight biological regulation the amyloid quaternary structure can be beneficial, as in the case of Pmel17, while dysregulation of normal protein function can result in aggregation and disease, as in the case of alpha-synuclein.