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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Dokumenter

DOI

  • Nelson Ferreira, Danish Research Institute of Translational Neuroscience
    • ,
  • Hjalte Gram
  • Zachary A Sorrentino, University of Florida
    • ,
  • Emil Gregersen
  • Sissel Ida Schmidt, Syddansk Universitet
    • ,
  • Lasse Reimer
  • Cristine Betzer, Danish Research Institute of Translational Neuroscience
    • ,
  • Clara Perez-Gozalbo, Aarhus Universitet
    • ,
  • Marjo Beltoja, Danish Research Institute of Translational Neuroscience
    • ,
  • Madhu Nagaraj
    • ,
  • Jie Wang, Jiangsu Univ, Jiangsu University, Inst Adv Mat
    • ,
  • Jan S Nowak
  • Mingdong Dong
  • Katarina Willén, Northwestern University
    • ,
  • Ersoy Cholak, Northwestern University
    • ,
  • Kaare Bjerregaard-Andersen, H Lundbeck & Co AS, Lundbeck Corporation, DMPK
    • ,
  • Nicolas Mendez, Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.
    • ,
  • Prakruti Rabadia, Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.
    • ,
  • Mohammad Shahnawaz, Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.
    • ,
  • Claudio Soto, Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.
    • ,
  • Daniel E Otzen
  • Morten Meyer, Syddansk Universitet
    • ,
  • Benoit I Giasson, University of Florida
    • ,
  • Marina Romero-Ramos
  • Poul Henning Jensen

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
Sider (fra-til)87-115
ISSN0001-6322
DOI
StatusUdgivet - jul. 2021

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