Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Nature. 2018 May;557(7706):558-563. doi: 10.1038/s41586-018-0104-4. Epub 2018 May 9.


In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology 1 -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoplasm / chemistry
  • Cytoplasm / metabolism*
  • Cytoplasm / pathology
  • Female
  • Humans
  • Lewy Bodies / chemistry
  • Lewy Bodies / metabolism*
  • Lewy Bodies / pathology*
  • Lewy Body Disease / metabolism*
  • Lewy Body Disease / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / chemistry
  • Neurons / metabolism*
  • Neurons / pathology
  • Oligodendroglia / chemistry
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Organ Specificity
  • Protein Folding
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / classification*
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein