Most amyloids are pathological. Many of them are related to neurodegenerative disorders such as Alzheimer’s and Parkinson’s (PD) that afflict the rapidly growing ageing populations. Despite the long association with pathology, examples exist of amyloids that maintain a benign nature and serve a specific function, challenging the traditional way that we have viewed amyloids. In this talk, I will present our insights into what may differentiate pathological from functional amyloid through our studies of α-synuclein (α-syn) and the repeat domain (RPT) of Pmel17, central players in PD and melanin biogenesis, respectively. Despite strong clinical evidence towards a link between α-syn and PD, pinpointing cellular initiation sites of protein aggregation and the specific pathogenic species have proven difficult. By contrast, RPT is sequestered in melanosomes, organelles where melanin is synthesized. RPT fibrils form strictly under acidic pH and completely dissolve at neutral pH, owing to the deprotonation of glutamic acids in its C-terminal amyloid core. This behavior contrasts strongly with that of α-syn, which can only be disassembled upon the harshest of treatments by chemical denaturants and non-physiological pH. Our working hypothesis is that this unique pH-reversible aggregation mechanism is an elegant way to control RPT fibril assembly and a potential safeguard against fibril escape into the cytosol. On the other hand, release of lysosomal-derived truncated α-syn fibrils has been shown seed fibril propagation <i>in vitro</i>. By identifying potential cellular modulators of amyloid formation, new approaches can be developed to mitigate amyloid associated cytotoxicity.

Amyloids in disease and biology

2019 Spring National Meeting

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