RT Journal Article SR Electronic T1 Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.04.12.439480 DO 10.1101/2021.04.12.439480 A1 Nguyen-Vi Mohamed A1 Julien Sirois A1 Janani Ramamurthy A1 Meghna Mathur A1 Paula Lépine A1 Eric Deneault A1 Gilles Maussion A1 Michael Nicouleau A1 Carol X.-Q. Chen A1 Narges Abdian A1 Vincent Soubannier A1 Eddie Cai A1 Harris Nami A1 Rhalena A. Thomas A1 Mahdieh Tabatabaei A1 Lenore K. Beitel A1 Karamjit Singh Dolt A1 Jason Karamchandani A1 Tilo Kunath A1 Edward A. Fon A1 Thomas M. Durcan YR 2021 UL http://biorxiv.org/content/early/2021/04/12/2021.04.12.439480.abstract AB SNCA, the first gene associated with Parkinson’s disease, encodes the α-synuclein (α-syn) protein, the predominant component within pathological inclusions termed Lewy bodies (LBs). The presence of LBs is one of the classical hallmarks found in the brain of patients with Parkinson’s disease, and LBs have also been observed in patients with other synucleinopathies. However, the study of α-syn 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 3D midbrain organoids (hMOs), 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 hMOs recapitulate key features of α-syn pathology observed in the brains of patients with synucleinopathies. In particular, we find that SNCA triplication hMOs express elevated levels of α-syn and exhibit an age-dependent increase in α-syn aggregation, manifested by the presence of both oligomeric and phosphorylated forms of α-syn. These phosphorylated α-syn aggregates were found in both neurons and glial cells and their time-dependent accumulation correlated with a selective reduction in dopaminergic neuron numbers. Thus, hMOs 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.Competing Interest StatementThe authors have declared no competing interest.