Patient-derived three-dimensional cortical neurospheres to model Parkinson’s disease

Raja, Waseem; Neves, Esther; Burke, Christopher; Jiang, Xin; Xu, Ping; Rhodes, Kenneth J.; Khurana, Vikram; Scannevin, Robert H.; Chung, Chee Yeun

doi:10.1371/journal.pone.0277532

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…Drug-induced models can recapitulate late-stage disease phenotypes and behaviors, but due to their acute onset, are inadequate to study the gradual accumulation of cellular dysfunction that precedes clinical presentation [13,14]. Advancements in induced pluripotent stem cell (iPSC) differentiation and CRISPR/Cas9 genome editing have led to the emergence of genetic cellular models of PD [15][16][17][18]. These models enable researchers to study the effects of genetic and environmental factors on specific human cell populations relevant to PD.…”

Section: Introductionmentioning

confidence: 99%

Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven byPRKNknockout

Goldman,

Kareva,

Sarrafha

et al. 2024

Preprint

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Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development and progression of many diseases and disorders, including neurodegenerative diseases and cancer. However, there is limited ability to continuously monitor these sub-cellular processes in real-time, and standardized assays to quantify these differences are lacking. Quantitative visualization of mitochondrial and lysosomal networks is crucial to better understand how these organelles are dysregulated during disease pathogenesis. To address this gap, we developed GEM-SCOPe (Genetically Encoded and Modular SubCellular Organelle Probes), an expandable toolbox of genetically encoded fluorescent markers, introduced into cell cultures by lentiviral transduction, which can be used to interrogate changes in proliferation and lysosomal and mitochondrial function in cell models of disease pathogenesis and progression. Genetically encoded fluorescent markers are a powerful tool to consistently visualize subcellular components in live cells without disrupting cellular processes. The fluorophores in GEM-SCOPe are designed to specifically localize to the desired organelle and illuminate information on localization, distribution, organelle turnover, and intracellular oxidative stress. GEM-SCOPe is modular; it can be expanded to include existing or new fluorophores and targeted to other subcellular structures or cell types, increasing the potential for genetically encoded fluorescent markers to probe any cell-model system or subcellular network in live cell cultures. To validate and illustrate the translational functionality of GEM-SCOPe, we applied it to track and quantify sub-cellular pathophysiology changes associated with Parkinson's Disease mediated by loss of function knockout of the PRKN gene. We expressed GEM-SCOPe in a PRKN knockout induced pluripotent stem cell line, differentiated into astrocytes and neurons, enabling us to track and quantify in real-time disease-associated changes in cellular proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. Collectively, we demonstrate that GEM-SCOPe is a powerful panel of live-cell fluorescent probes that provide critical insight into the subcellular mechanisms underlying Parkinson's disease in human astrocytes and neurons. GEM-SCOPe can be applied to a diverse range of cellular models of disease to glean an understanding of the underlying mechanisms that promote disease onset and progression.

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Section: Introductionmentioning

confidence: 99%

Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven byPRKNknockout

Goldman,

Kareva,

Sarrafha

et al. 2024

Preprint

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Microcystin-LR Exposure Damages Neurons by Inducing α-Syn Aggregation via MAPK4/GATA2/SNCA and PP2A/GRKs Pathways

Yan,

Wu,

et al. 2024

Mol Neurobiol

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CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease

et al. 2023

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Since its discovery in 2012, CRISPR Cas9 has been tried as a direct treatment approach to correct the causative gene mutation and establish animal models in neurodegenerative disorders. Since no strategy developed until now could completely cure Parkinson's disease (PD), neuroscientists aspire to use gene editing technology, especially CRISPR/Cas9, to induce a permanent correction in genetic PD patients expressing mutated genes. Over the years, our understanding of stem cell biology has improved. Scientists have developed personalized cell therapy using CRISPR/Cas9 to edit embryonic and patient-derived stem cells ex-vivo. This review details the importance of CRISPR/Cas9-based stem cell therapy in Parkinson's disease in developing PD disease models and developing therapeutic strategies after elucidating the possible pathophysiological mechanisms. Graphical Abstract

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Patient-derived three-dimensional cortical neurospheres to model Parkinson’s disease

Cited by 4 publications

References 30 publications

Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven byPRKNknockout

Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven byPRKNknockout

Microcystin-LR Exposure Damages Neurons by Inducing α-Syn Aggregation via MAPK4/GATA2/SNCA and PP2A/GRKs Pathways

CRISPR/Cas9 assisted stem cell therapy in Parkinson's disease

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