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

Nelson Ferreira*, Hjalte Gram, Zachary A. Sorrentino, 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-Andersen, Nicolas Mendez, Prakruti Rabadia, Mohammad Shahnawaz, Claudio SotoDaniel E. Otzen, Ümit Akbey, Morten Meyer, Benoit I. Giasson, Marina Romero-Ramos, Poul Henning Jensen

*Kontaktforfatter for dette arbejde

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Abstrakt

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

OriginalsprogEngelsk
TidsskriftActa Neuropathologica
Vol/bind142
Udgave nummer1
Sider (fra-til)87-115
ISSN0001-6322
DOI
StatusUdgivet - jul. 2021

Bibliografisk note

Funding Information:
The study was supported by Lundbeck Foundation grants R223-2015-4222 for PHJ, R248-2016-2518 for Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Aarhus University, Denmark, Postdoctoral Fellowship R171-2014-591 to N.F. and R276-2018-671 to D.E.O and J.S.N. The National Institutes of Health R01NS100876 to B.I.G., Danish Council for Independent Research Grant ID: 6108-00396B to M.D., a Predoctoral Fellowship F30AG063446 to Z.A.S. This work was funded in part by a grant from the Michael J Fox Foundation for Parkinson’s Research to C.S. The authors would like to thank Marie Vestergaard for graphical data analysis with R programming and Jette Bank Lauridsen and Gitte Ulberg Toft for excellent technical assistance.

Publisher Copyright:
© 2021, The Author(s).

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