Lewy Body-like Pathology and Loss of Dopaminergic Neurons in Midbrain Organoids Derived from Familial Parkinson’s Disease Patient

Andrea Becerra-Calixto, Abhisek Mukherjee, Santiago Ramirez, Sofia Sepulveda, Tirthankar Sinha, Rabab Al-Lahham, Nicole De Gregorio, Camila Gherardelli, Claudio Soto

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson’s disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of αSyn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. We demonstrated that hMBOs generated from induced pluripotent stem cells (hiPSCs), derived from a familial PD (fPD) patient carrying αSyn gene (SNCA) triplication accumulate pathological αSyn over time. These cytoplasmic inclusions spatially and morphologically resembled diverse stages of LB formation and were composed of key markers of LBs. Importantly, the progressive accumulation of pathological αSyn was paralleled by the loss of DA neurons and elevated apoptosis. The model developed in this study will complement the existing in vitro models of PD and will provide a unique platform to study the spatiotemporal events governing LB formation and their relation with neurodegeneration. Furthermore, this model will also be beneficial for in vitro screening and the development of therapeutic compounds.

Original languageEnglish (US)
Article number625
JournalCells
Volume12
Issue number4
DOIs
StatePublished - Feb 2023
Externally publishedYes

Keywords

  • 3D models
  • Lewy body disease
  • Parkinson’s disease
  • human midbrain-like organoids

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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