α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice

• Published in: Nature communications 2023-10, Vol.14 (1), p.6892-17, Article 6892
• Main Authors: Uemura, Norihito, Marotta, Nicholas P., Ara, Jahan, Meymand, Emily S., Zhang, Bin, Kameda, Hiroshi, Koike, Masato, Luk, Kelvin C., Trojanowski, John Q., Lee, Virginia M.-Y.
• Format: Article
• Language: English
• Subjects: 631/378/1689/1718; 631/378/1689/364; 631/378/1934; 64/110; 64/60; Aggregates; Aging; alpha-Synuclein - metabolism; Amplification; Animal models; Animals; Brain; Brain - metabolism; Cytology; Dementia; Disease; Drug dosages; Fibrillogenesis; Fibrils; Humanities and Social Sciences; Humans; Injection; Latency; Lewy bodies; Lewy Bodies - metabolism; Lewy body disease; Lewy Body Disease - pathology; Male; Mice; Morphology; multidisciplinary; Pathology; Protein seeding; Science; Science (multidisciplinary); Structure-function relationships; Synuclein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42705-5

Extraction of α-Synuclein (αSyn) aggregates from Lewy body disease (LBD) brains has been widely described yet templated fibrillization of LB-αSyn often fails to propagate its structural and functional properties. We recently demonstrated that aggregates amplified from LB-αSyn (ampLB) show distinct biological activities in vitro compared to human αSyn preformed fibrils (hPFF) formed de novo. Here we compare the in vivo biological activities of hPFF and ampLB regarding seeding activity, latency in inducing pathology, distribution of pathology, inclusion morphology, and cell-type preference. Injection of ampLB into mice expressing only human αSyn (male Thy1: SNCA / Snca –/– mice) induced pathologies similar to those of LBD subjects that were distinct from those induced by hPFF-injection or developing spontaneously with aging. Importantly, αSyn aggregates in ampLB-injected Thy1: SNCA / Snca –/– mice maintained the unique biological and conformational features of original LB-αSyn. These results indicate that ampLB-injection, rather than conventional PFF-injection or αSyn overexpression, faithfully models key aspects of LBD. α-Synuclein aggregates in Lewy bodies (LBs) have not been widely used for research due to the limited availability of diseased brains. Here, the authors report a mouse model that recapitulates LB diseases using the LB amplification method.