Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by <scp>2‐Hydroxypropyl‐β‐Cyclodextrin</scp> Treatment

Jarazo, Javier; Barmpa, Kyriaki; Modamio, Jennifer; Saraiva, Cláudia; Sabaté-Soler, Sònia; Rosety, Isabel; Griesbeck, Anne; Skwirblies, Florian; Zaffaroni, Gaia; Smits, Lisa M.; Su, Ji-Hui; Arias, Jonathan; Walter, Jonas; Gomez-Giro, Gemma; Monzel, Anna S.; Qing, Xiaobing; Vitali, Armelle; Cruciani, Gérald; Boussaad, Ibrahim; Brunelli, F.; Jäger, Christian; Raković, Aleksandar; Li, Wen; Yuan, Lin; Berger, Emanuel; Arena, Giuseppe; Bolognin, Silvia; Schmidt, Ronny; Schröder, Christoph; Antony, Paul; Klein, Christine; Krüger, Rejko; Seibler, Philip; Schwamborn, Jens Christian

doi:10.1002/mds.28810

Cited by 54 publications

(59 citation statements)

References 78 publications

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“…Reactive astrocytes increase PINK1 protein expression (Table 1; Choi et al, 2016;Jarazo et al, 2022). Astrocytes with PINK1 loss of function increased neuroinflammation and lacked physiological support to neurons (Leites and Morais, 2021).…”

Section: Pten-induced Putative Kinase 1/parkin/dj-1 and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.

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Section: Pten-induced Putative Kinase 1/parkin/dj-1 and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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“…While HP-β-CD has been established as a promising excipient in pharmacology, its repurposed application for enhancing autophagic capacity in PD organoids has only been reported recently. 39 In an attempt to demonstrate the ability of our multi-sensor integrated midbrain organoid-on-a-chip platform to detect phenotypic rescue, exposure of 3×SNCA hMOs to 5 μM of HP-β-CD was assessed. To that end, dopamine release and respiratory activity of healthy, 3×SNCA, as well as HP-β-CD-treated 3xSNCA hMOs were investigated in a final time-resolved comparative study.…”

Section: Resultsmentioning

confidence: 99%

“…46 Since the observed pathological phenotypes can be linked, at least in part, to impaired autophagy, the repurposed excipient HP-β-CD, which has previously been shown to induce rescue effects in a PD organoid model with mutations in PINK1, was used to challenge the ability of our multi-sensor integrated midbrain organoid-on-a-chip platform. 39 Intriguingly, integrated oxygen sensing alone pointed towards significant rescue effects expressed by a marked increase in normalized oxygen demands for HP-β-CD-treated hMOs compared to PD controls. These effects were further verified by immunofluorescence analysis, revealing significant reductions in aggregated α-synuclein, distinct improvements of several mitochondrial characteristics as well as significantly enlarged populations of TH-positive dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 97%

“…[36][37][38] We have previously shown that the compound 2-hydroxypropyl β-cyclodextrin (HP-β-CD) can rescue PD-related phenotypes in a personalized PD model carrying biallelic pathogenic variants in the PINK1 gene by elevating the neuronal autophagy and mitophagy capacity. 39 Autophagy dysregulation has been implicated in many genetic models of PD including that of α-synuclein, rendering HP-β-CD, an ideal candidate for the evaluation of the microfluidic platform. Thus, in our final set of experiments, the multi-sensor integrated platform is employed to investigate the dynamic exposure of HP-β-CD on PD onset and progression.…”

Section: Introductionmentioning

confidence: 99%

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Development of a multi-sensor integrated midbrain organoid-on-a-chip platform for studying Parkinson’s disease

Spitz

Bolognin²,

Brandauer³

et al. 2022

Preprint

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Due to its ability to recapitulate key pathological processes in vitro, midbrain organoid technology has significantly advanced the modeling of Parkinson's disease over the last few years. However, some limitations such as insufficient tissue differentiation and maturation, deficient nutrient supply, and low analytical accessibility persist, altogether restricting the technology from reaching its full potential. To overcome these drawbacks, we have developed a multi-sensor integrated organ-on-a-chip platform capable of monitoring the electrophysiological, respiratory, and dopaminergic activity of human midbrain organoids. Our study showed that microfluidic cultivation resulted in a marked reduction in necrotic core formation, improved tissue differentiation as well as the recapitulation of key pathological hallmarks. Non-invasive monitoring employing an orthogonal sensing strategy revealed a clear time dependency in the onset of Parkinson's disease-related phenotypes, reflecting the complex progression of the neurodegenerative disorder. Furthermore, drug-mediated rescue effects were observed after treatment with the repurposed compound 2-hydroxypropyl β-cyclodextrin, highlighting the platform's potential in the context of drug screening applications as well as personalized medicine.

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“…Compared to the corrected organoids, the patient organoids recapitulate the key PD features, consistent with the fact that mutation of the PINK1 gene alone is sufficient to cause PD. Using both types of midbrain organoids as a platform, the selected compounds from the mouse model were tested [ 65 ]. In a separate study, human mid-brain-like organoids (hMLOs) harboring control or mutant DNAJC6 were generated to model the early-onset PD caused by a DNAJC6 mutation.…”

Section: Brain Organoid-based Modeling Of Neurological Disordersmentioning

confidence: 99%

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening

Seong

et al. 2022

Stem Cells International

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Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer’s disease (AD), Parkinson’s disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.

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Parkinson's Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2‐Hydroxypropyl‐β‐Cyclodextrin Treatment

Cited by 54 publications

References 78 publications

Astrocytes in Neurodegeneration: Inspiration From Genetics

Astrocytes in Neurodegeneration: Inspiration From Genetics

Development of a multi-sensor integrated midbrain organoid-on-a-chip platform for studying Parkinson’s disease

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening

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