Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression

Alise Zagare, Kyriaki Barmpa, Semra Smajic, Lisa M. Smits, Kamil Grzyb, Anne Grünewald, Alexander Skupin, Sarah L. Nickels*, Jens C. Schwamborn*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

Human brain organoid models that recapitulate the physiology and complexity of the human brain have a great potential for in vitro disease modeling, in particular for neurodegenerative diseases, such as Parkinson disease. In the present study, we compare single-cell RNA-sequencing data of human midbrain organoids to the developing human embryonic midbrain. We demonstrate that the in vitro model is comparable to its in vivo equivalents in terms of developmental path and cellular composition. Moreover, we investigate the potential of midbrain organoids for modeling early developmental changes in Parkinson disease. Therefore, we compare the single-cell RNA-sequencing data of healthy-individual-derived midbrain organoids to their isogenic LRRK2-p.Gly2019Ser-mutant counterparts. We show that the LRRK2 p.Gly2019Ser variant alters neurodevelopment, resulting in an untimely and incomplete differentiation with reduced cellular variability. Finally, we present four candidate genes, APP, DNAJC6, GATA3, and PTN, that might contribute to the LRRK2-p.Gly2019Ser-associated transcriptome changes that occur during early neurodevelopment.

Original languageEnglish
Pages (from-to)311-327
Number of pages17
JournalAmerican Journal of Human Genetics
Volume109
Issue number2
DOIs
Publication statusPublished - 3 Feb 2022
Externally publishedYes

Keywords

  • LRRK2-G2019S
  • Parkinson disease
  • midbrain organoids
  • neurodevelopment
  • single-cell RNA sequencing

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