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Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations
Junghyun Jo1,2, Lin Yang1, Hoang-Dai Tran1,3
1Genome Institute of Singapore, Singapore, Singapore.
Annals of Neurology
|July 21, 2021
Summary
Human midbrain organoids with glucocerebrosidase deficiency and alpha-synuclein overexpression model Parkinson disease. This study shows these organoids develop Lewy body-like inclusions, aiding Parkinson
Area of Science:
- Neuroscience
- Stem Cell Biology
- Genetics
Background:
- Parkinson disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein aggregation and Lewy body formation.
- Genetic factors, including mutations in the glucocerebrosidase (GBA1) gene and alpha-synuclein (SNCA) gene, are significant risk factors for PD.
- Human midbrain-like organoids (hMLOs) offer a promising in vitro model to study PD pathogenesis.
Purpose of the Study:
- To investigate genotype-to-phenotype relationships in Parkinson disease using hMLOs.
- To recapitulate alpha-synuclein and Lewy body-related pathologies in a human organoid model.
- To elucidate the mechanisms underlying neurodegeneration and Lewy body formation in PD.
Main Methods:
- Generation and characterization of hMLOs from isogenic pluripotent stem cells with GBA1 deficiency and/or SNCA overexpression.
- Induction of Lewy body-like inclusions in hMLOs through genetic perturbations and pharmacological treatment.
- Analysis of alpha-synuclein aggregation and Lewy body formation in patient-derived and engineered hMLOs.
Main Results:
- Loss of glucocerebrosidase combined with wild-type alpha-synuclein overexpression leads to substantial accumulation of detergent-resistant, beta-sheet-rich alpha-synuclein aggregates.
- Lewy body-like inclusions, containing alpha-synuclein and ubiquitin, were formed in hMLOs and share morphological similarities with those found in PD patients.
- Impaired glucocerebrosidase function promotes Lewy body-like inclusion formation in hMLOs derived from SNCA triplication patients.
Conclusions:
- hMLOs harboring key PD risk factors (GBA1 deficiency and SNCA overproduction) provide a valuable model for studying PD.
- This model facilitates further elucidation of the progressive Lewy body formation mechanisms in Parkinson disease.
- The study highlights the utility of hMLOs in understanding the complex interplay of genetic factors in PD pathogenesis.
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