Modeling Parkinson’s disease in midbrain-like organoids

Smits, Lisa M.; Reinhardt, Lydia; Reinhardt, Peter; Glatza, Michael; Monzel, Anna S.; Stanslowsky, Nancy; Rosato-Siri, Marcelo D.; Zanon, Alessandra; Antony, Paul; Bellmann, Jessica; Nicklas, Sarah; Hemmer, Kathrin; Qing, Xiaobing; Berger, Emanuel; Kalmbach, Norman; Ehrlich, Marc; Bolognin, Silvia; Hicks, Andrew A.; Wegner, Florian; Sterneckert, Jared; Schwamborn, Jens Christian

doi:10.1038/s41531-019-0078-4

Cited by 230 publications

(289 citation statements)

References 22 publications

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“…In vivo models of seeded α-syn aggregation are slow and costly, and in vitro cell-based models developed to facilitate mechanistic investigation and drug screening lack the complexity of nervous tissue (Gribaudo et al, 2019), (Volpicelli-Daley, Luk, & Lee, 2014), (Smits et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The model takes advantage of the organotypic hippocampal slice culture that for decades has been used for electrophysiological analyses (Dunwiddie & Lynch, 1978). It possesses three synaptically connected neuronal populations located in a developmentally evolved brain 13 structure embedded in an active matrix of glia cells, and it is thus outperforms currently available two-and even three-dimensional in vitro culture systems (Smits et al, 2019), (Amin & Paşca, 2018). The model is based on microinjection of α-syn PFFs into the DG.…”

Section: Discussionmentioning

confidence: 99%

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Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates

Elfarrash

Jensen

Ferreira

et al. 2019

Preprint

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Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by injection of preformed α-synuclein filaments (PFFs). PFF injection at dentate gyrus templates the endogenous α-synuclein to form aggregates in axons and cell bodies that spread to CA3 and CA1 regions. Aggregates were insoluble and phosphorylated at serine 129, recapitulating Lewy pathology features found in Parkinson's disease and other synucleinopathies. The spreading of the aggregates were favoring the anterograde direction in the slice model. The model allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using adeno-associated viral (AAV) vector in α-synuclein knockout slices. Processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine 129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated by using viral vectors allow testing of hypotheses on mechanisms involved in formation of α-synuclein aggregates and their prion-like spreading.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates

Elfarrash

Jensen

Ferreira

et al. 2019

Preprint

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“…The development of regionally restricted midbrain-specific organoids suggests their potential to model Parkinson's disease (Jo et al, 2016;Monzel et al, 2017). Two recent studies show that genetically modified and patient-derived midbrain organoids harboring the PD-associated LRRK2-G2019S mutation manifest degenerative phenotypes and decreased complexity of dopaminergic neurons (Kim et al, 2019;Smits et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Due to architecturally complex heterotypic organization, comprehensive image analysis in organoids is challenging. Building on this, we developed methods to automatically acquire and process data from high-content imaging in organoids, which has been successfully demonstrated in brain organoids (Smits et al, 2019) and 3D microfluidic cultures (Bolognin et al, 2019). In this study, we further refined this pipeline with optimized high-content image data analysis tools in a neurotoxininduced PD organoid model.…”

Section: Introductionmentioning

confidence: 99%

Machine learning-assisted neurotoxicity prediction in human midbrain organoids

Monzel

Hemmer

Mukendi

et al. 2019

Preprint

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AbstractA major challenge in the field of neurodegenerative diseases is the poor translation of pre-clinical models to clinical applications. The human brain is an immensely complex structure, which makes it difficult to recapitulate its development, function and disorders. In the recent years, brain organoids derived from human induced pluripotent stem cells have risen as novel tools to study neurodegenerative diseases such as Parkinson’s disease (PD). PD is a multifactorial disorder, with aging, genetics and environmental factors as key etiological elements. The majority of the PD cases are idiopathic and proposed to result from a complex interaction between genetic predisposition and environmental exposure. Consequently, the identification of potentially disease causing environmental factors is of critical importance. Organoids, as complex multi-cellular tissue proxies, are an ideal tool to study cellular response to environmental changes. However, with increasing complexity of the system, usage of quantitative tools becomes challenging. This led us to develop an automated high-content image analysis pipeline for image-based cell profiling in the organoid system. Here, we introduce a midbrain organoid system that recapitulates features of neurotoxin-induced PD, representing a platform for machine-learning-assisted prediction of neurotoxicity in high-content imaging data. This model is a valuable tool for advanced in vitro PD modeling and for the screening of putative neurotoxic compounds.

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“…These organ-like structures contain different cell types in a spatially organized fashion, recapitulating at least some of the main functions of the respective organ. Importantly, they have been proven valid models for human diseases (Clevers, 2016;Lancaster et al, 2013;Smits et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

Jarazo

Barmpa

Rosety

et al. 2019

Preprint

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The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.

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Modeling Parkinson’s disease in midbrain-like organoids

Cited by 230 publications

References 22 publications

Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates

Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates

Machine learning-assisted neurotoxicity prediction in human midbrain organoids

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

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