4.0 Article

Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy

Journal

BRAIN COMMUNICATIONS
Volume 3, Issue 4, Pages -

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/braincomms/fcab223

Keywords

human midbrain organoids; iPSCs; oc-synuclein; Parkinson's disease

Funding

  1. McGill Healthy Brains for Healthy Lives (HBHL) initiative
  2. Consortium Quebecois sur la Decouverte du Medicament (CQDM) Fonds d'acceleration des collaborations en sante (FACS) programme
  3. Sebastian and Ghislaine Van Berkom Foundation
  4. Canadian Institutes of Health Research (CIHR) [FDN-154301]
  5. Canada Research Chair (Tier 1) in Parkinson's Disease
  6. Canadian Consortium on Neurodegeneration in Aging (CCNA)
  7. CIHR [PJT-169095]
  8. Ellen Foundation
  9. Parkinson's Canada
  10. Medical Research Council [MR/K017276/1]
  11. Fonds de recherche du Quebec-Sante (FRSQ)
  12. Parkinson Canada
  13. Parkinson Quebec
  14. MRC [MR/K017276/1] Funding Source: UKRI

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This study used three-dimensional midbrain organoids differentiated from human-induced pluripotent stem cells to recapitulate key features of alpha-synuclein pathology in patients with synucleinopathies. The SNCA triplication human midbrain organoids express elevated levels of alpha-synuclein and exhibit an age-dependent increase in alpha-synuclein aggregation, providing a powerful system to study the pathogenesis of synucleinopathies.
SNCA, the first gene associated with Parkinson's disease, encodes the a-synuclein protein, the predominant component within pathological inclusions termed Lewy bodies. The presence of Lewy bodies is one of the classical. hallmarks found in the brain of patients with Parkinson's disease, and Lewy bodies have also been observed in patients with other synucleinopathies. However, the study of alpha-synuclein pathology in cells has relied largely on two-dimensional culture models, which typically lack the cellular diversity and complex spatial environment found in the brain. Here, to address this gap, we use three-dimensional midbrain organoids, differentiated from human-induced pluripotent stem cells derived from patients carrying a triplication of the SNCA, gene and from CRISPR/Cas9 corrected isogenic control iPSCs. These human midbrain organoids recapitulate key features of alpha-synuclein pathology observed in the brains of patients with synudeinopathies. In particular, we find that SNCA triplication human midbrain organoids express elevated levels of alpha-synuclein and exhibit an age-dependent increase in alpha-synudein aggregation, manifested by the presence of both oligomeric and phosphorylated forms of alpha-synuclein. These phosphorylated alpha-synudein aggregates were found in both neurons and glial cells and their time-dependent accumulation correlated with a selective reduction in dopaminergic neuron numbers. Thus, human midbrain organoids from patients carrying SNCA gene multiplication can reliably model key pathological features of Parkinson's disease and provide a powerful system to study the pathogenesis of synucleinopathies.

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