Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

• DOI: 10.1007/s00401-021-02316-0
• Publication Date: 2021-05-12T12:02:58Z
• Authors: Nelson Ferreira; Hjalte Gram; Zachary A. Sorren...; Emil Gregersen; Sissel Ida Schmidt; Lasse Reimer; Cristine Betzer; Clara Perez-Gozalbo; Marjo Beltoja; Madhu Nagaraj; Jie Wang; Jan S. Nowak; Mingdong Dong; Katarina Willén; Ersoy Cholak; Kaare Bjerregaard...; Nicolas Mendez; Prakruti Rabadia; Mohammad Shahnawaz; Claudio Soto; Daniel E. Otzen; Ümit Akbey; Morten Meyer; Benoit I. Giasson; Marina Romero-Ramos; Poul Henning Jensen
• Keywords: Strain (injury)

Abstract Pathology consisting of intracellular aggregates alpha-Synuclein (α-Syn) spread through the nervous system in a variety neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple atrophy. The discovery structurally distinct α-Syn polymorphs, so-called strains, supports hypothesis where strain-specific structures are templated into formed by native α-Syn. These strains hypothesised to dictate spreading pathology tissue cellular impact aggregates, thereby contributing clinical phenotypes. Here, we present evidence novel strain induced atrophy-associated oligodendroglial protein p25α. Using an array biophysical, biochemical, cellular, vivo analyses, demonstrate that compared alone, substoichiometric concentration p25α redirects aggregation unique α-Syn/p25α different structure enhanced prodegenerative properties. larger inclusions human dopaminergic neurons. In , intramuscular injection preformed fibrils (PFF) PFF resulted shortened life span anatomical distribution inclusion brain A53T transgenic (line M83) mouse. Investigation stem extracts end-stage mice demonstrated more aggressive phenotype was associated increased load based on Förster resonance energy transfer immunoassay reduced aggregate seeding activity misfolding cyclic amplification assay. When injected unilaterally striata wild-type mice, more-pronounced motoric than exhibited “tropism” for nigro-striatal neurons PFF. Overall, our data support whereby is responsible generating highly