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Jan Stanislaw Nowak

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Nelson Ferreira
  • Hjalte Gram
  • Zachary A Sorrentino, Univ Florida, Florida State University System, University of Florida, Florida Museum Nat Hist
  • ,
  • Emil Gregersen
  • Sissel Ida Schmidt, University of Southern Denmark
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  • Lasse Reimer
  • Cristine Betzer
  • Clara Perez-Gozalbo, Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • Marjo Beltoja, Danish Research Institute of Translational Neuroscience
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  • Madhu Nagaraj
  • ,
  • Jie Wang, Jiangsu Univ, Jiangsu University, Inst Adv Mat
  • ,
  • Jan S Nowak
  • Mingdong Dong
  • Katarina Willén, Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University
  • ,
  • Ersoy Cholak, Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University
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  • Kaare Bjerregaard-Andersen, H Lundbeck & Co AS, Lundbeck Corporation, DMPK
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  • 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, University of Southern Denmark
  • ,
  • Benoit I Giasson, Univ Florida, Florida State University System, University of Florida, Florida Museum Nat Hist
  • ,
  • 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.

Original languageEnglish
JournalActa Neuropathologica
Volume142
Pages (from-to)87-115
ISSN0001-6322
DOIs
Publication statusPublished - Jul 2021

    Research areas

  • Multiple system atrophy (MSA), P25α, Protein aggregation, Strains, Tubulin polymerisation-promoting protein (TPPP), Α-Synuclein

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