Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson's Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

Cells. 2021 Sep 13;10(9):2402. doi: 10.3390/cells10092402.


Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.

Keywords: Lewy bodies; Parkinson’s disease; dopaminergic neurons; iPSC; mitochondria; α-synuclein aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Cell Differentiation*
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Synucleinopathies / etiology
  • Synucleinopathies / metabolism
  • Synucleinopathies / pathology*
  • Young Adult
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • SNCA protein, human
  • alpha-Synuclein
  • Dopamine