α-Synuclein: Multiple system atrophy prions Amanda L. Woerman1,2, Joel C. Watts4, Atsushi Aoyagi1,6, Kurt Giles1,2, Lefkos T. Middleton5, and Stanley B. Prusiner1,2,3 1Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, California 94158 2Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, California 94158 3Department of Biochemistry and Biophysics, University of California San Francisco, California 94158 4Tanz Centre for Research in Neurodegenerative Diseases and Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5T 2S8 5Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London SW7 2AZ, United Kingdom 6Daiichi Sankyo Co., Ltd., Tokyo, 140-8710, Japan Correspondence:
[email protected] Running title: α-Synuclein prions in multiple system atrophy ABSTRACT Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α- synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA- derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients.