Lightning Talk & Poster Australasian Extracellular Vesicles Conference 2018

Loss of ultrastructure ablates exosome-induced acceleration of α-synuclein fibrillization (#56)

Cathryn Ugalde 1 2 3 , Mitch Shambrook 2 , Bradley M Coleman 1 , Vicki Lawson 4 , David Finkelstein 3 , Andrew F Hill 2
  1. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Vic, Australia
  2. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
  3. Howard Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
  4. Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

The misfolding and aggregation of the intrinsically disordered protein, α-synuclein (αsyn), in the central nervous system is associated with a group of neurodegenerative disorders referred to as synucleinopathies. This includes Parkinson’s disease, dementia with Lewy Body and Multiple System Atrophy, among others. The mechanisms underlying αsyn misfolding are poorly elucidated, however a persistent observation is the ability of small unilamellar vesicles (SUVs) composed of synthetic lipids to modulate the protein’s folding. Here we sought to investigate the ability of lipid-rich exosomes to alter αsyn fibrillization. We show that exosomes influence the misfolding of αsyn; enhancing the rate of fibrillization and changing the biophysical properties of species formed. To determine what component of exosomes contributes to this effect, exosomes were chemically modified by treatment with methanol, or a combination of methanol and sarkosyl. These treatments altered the ultrastructure of the exosomes without changing the protein cargo. Critically, these modified exosomes lost the ability to influence αsyn fibrillization. This work shows that exosomes are powerful modulators of αsyn fibrillization that is dependent on the vesicle’s ultrastructure and/or lipid content. Furthermore, this work implicates exosomes as potential agents to trigger or contribute to αsyn misfolding in the synucleinopathy disorders.