A High-Content Screen Identifies TPP1 and Aurora B as Regulators of Axonal Mitochondrial Transport

Shlevkov, Evgeny; Basu, Himanish; Bray, Mark-Anthony; Sun, Zheng; Wei, Wei; Apaydin, Kaan; Karhohs, Kyle W.; Chen, Pin-Fang; Smith, Janell L.M.; Wiskow, Ole; Roet, Kasper C.D.; Huang, Xuan; Eggan, Kevin; Carpenter, Anne E.; Kleiman, Robin J.; Schwarz, Thomas L.

doi:10.1016/j.celrep.2019.08.035

Cited by 35 publications

(40 citation statements)

References 69 publications

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“…Although the latter is preferred due to therapeutic potential, this result suggests that the virtual screening strategy, applied to a larger set of compounds, might identify novel motility-promoting compounds. We found 3 of the 23 compounds suppress motility but do not decrease mitochondrial membrane potential; this is a much higher hit rate (13.0%) than in our prior screen of 3,280 bioactive compounds, which yielded two such compounds (0.06%) (34). ch a l, 1a).…”

Section: Discovery Of Hits Impacting Ppargc1a (Pgc-1α) Overexpression Phenotypesmentioning

confidence: 56%

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Virtual screening for small molecule pathway regulators by image profile matching

Rohban

Fuller

Tan

et al. 2021

Preprint

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Identifying chemical regulators of biological pathways is currently a time-consuming bottleneck in developing therapeutics and small-molecule research tools. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to a disease of interest. Here, we instead use a broad, virtual screening approach that matches compounds to pathways based on phenotypic information in public data. Our computational strategy efficiently uncovered small molecule regulators of three pathways, containing p38ɑ (MAPK14), YAP1, or PPARGC1A (PGC-1α). We first selected genes whose overexpression yielded distinct image-based profiles in the Cell Painting assay, a microscopy assay involving six stains that label eight cellular organelles/components. To identify small molecule regulators of pathways involving those genes, we used publicly available Cell Painting profiles of 30,616 small molecules to identify compounds that yield morphological effects either positively or negatively correlated with image-based profiles for specific genes. Subsequent assays validated compounds that impacted the predicted pathway activities. This image profile-based drug discovery approach could transform both basic research and drug discovery by identifying useful compounds that modify pathways of biological and therapeutic interest, thus using a computational query to replace certain customized labor- and resource-intensive screens.

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Section: Discovery Of Hits Impacting Ppargc1a (Pgc-1α) Overexpression Phenotypesmentioning

confidence: 56%

“…High content mitochondrial motility screen: We used our previously published assay to assess mitochondrial motility 36 . Briefly, we plated E18 rat cortical neurons in the middle 60 wells of 96 well plates (Greiner) -40,000 cells per well in 150 µl enriched Neurobasal media.…”

Section: Ppargc1a (Pgc-1α) Experimentsmentioning

confidence: 99%

Virtual screening for small molecule pathway regulators by image profile matching

Rohban

Fuller

Tan

et al. 2021

Preprint

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“…We speculate that the loss of mitochondria from axonal terminals in Miro1 KO cells could be the consequence of defective protein-protein interactions with the tethering machinery, resulting in the inability of mitochondria to be retained in the presynaptic space. Mitochondrial transport on actin filaments mediates local distribution along the axon and destabilisation of F-actin reduces mitochondrial docking Hollenbeck, 2003, 2004;Hirokawa et al, 2010;Shlevkov et al, 2019;Smith and Gallo, 2018).…”

Section: Discussionmentioning

confidence: 99%

Miro1-dependent mitochondrial dynamics in parvalbumin interneurons

Kontou

Antonoudiou

Podpolny

et al. 2021

eLife

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The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca²⁺-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter network activity in the mouse brain. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization while PV+ interneuron mediated inhibition remained intact. These changes were accompanied by an increase in the ex vivo hippocampal γ-oscillation (30 – 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

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Section: Pathways and Proteins Regulating T-nepc Phenotype And Thementioning

confidence: 99%

“…Interestingly, also AURKB has been associated with neuronal functions through the discovery of a previously unrecognized role for AURKB as a regulator of mitochondrial trafficking in neurons [ 95 ]. This finding was supported by the observation that AURKB knockdown promoted mitochondrial axonal transport in both rat hippocampal neurons and in induced pluripotent stem cell (iPSC)-derived human cortical neurons [ 95 ]. As cancer-associated kinases, both AURKA and AURKB have been extensively studied in search for new potential small molecular inhibitors that could be used in anti-cancer therapy (reviewed by Borisa and Bhatt) [ 96 ].…”

Section: Pathways and Proteins Regulating T-nepc Phenotype And Thementioning

confidence: 99%

Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Kaarijärvi

Kaljunen

Ketola

2021

Cancers

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Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

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A High-Content Screen Identifies TPP1 and Aurora B as Regulators of Axonal Mitochondrial Transport

Cited by 35 publications

References 69 publications

Virtual screening for small molecule pathway regulators by image profile matching

Virtual screening for small molecule pathway regulators by image profile matching

Miro1-dependent mitochondrial dynamics in parvalbumin interneurons

Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

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