Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases

• DOI: 10.1126/sciadv.adq3539
• Publication Date: 2024-11-01T17:59:14Z
• Authors: Arpine Sokratian; Ye Zhou; Meltem Tatli; Kevin J. Burbidge; Enquan Xu; Elizabeth Viverette; Sonia Donzelli; Addison M. Duda; Yuan Yuan; Huizhong Li; Samuel Strader; Nirali Patel; Lauren Shiell; Tuyana Malankhanova; Olivia Chen; Joseph R. Mazzulli; Lalith Perera; Henning Stahlberg; Mario Borgnia; Alberto Bartesaghi; Hilal A. Lashuel; Andrew B. West
• Keywords: Lewy Body Disease; Models, Molecular; Neurons; Amyloid; Brain; Parkinson Disease; Mice, Transgenic; Multiple System Atrophy; Mice; Disease Models, Animal; alpha-Synuclein/metabolism; alpha-Synuclein/chemistry; Humans; Animals; Mice; Lewy Body Disease/metabolism; Lewy Body Disease/pathology; Parkinson Disease/metabolism; Parkinson Disease/pathology; Amyloid/metabolism; Amyloid/chemistry; Mice, Transgenic; Models, Molecular; Multiple System Atrophy/metabolism; Multiple System Atrophy/pathology; Disease Models, Animal; Neurons/metabolism; Neurons/pathology; Brain/metabolism; Brain/pathology; alpha-Synuclein; Humans; Animals; Neuroscience

The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson’s disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.