Dataset Information

Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.

ABSTRACT: Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled by monocultures. However, cocultures are difficult to use and analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures to model inflammatory neurodegeneration, live-cell stains, and automated classification of neurons, astrocytes or microglia using open-source software. Out of 227 compounds with known bioactivities, 29 protected against lipopolysaccharide-induced neuronal loss, including drugs affecting adrenergic, steroid, inflammatory and MAP kinase signaling. The screen also identified physiological compounds, such as noradrenaline and progesterone, that protected and identified neurotoxic compounds, such as a TLR7 agonist, that induced microglial proliferation. Most compounds used here have not been tested in a neuron-glia coculture neurodegeneration assay previously. Thus, combining a complex cellular disease model with high-content screening of known compounds and automated image analysis allows identification of important biology, as well as potential targets and drugs for treatment.

SUBMITTER: Birkle TJY

PROVIDER: S-EPMC10973195 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.

Birkle Timothy J Y TJY Willems Henriette M G HMG Skidmore John J Brown Guy C GC

iScience 20240308 4

Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled by monocultures. However, cocultures are difficult to use and analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures to model inflammatory neurodegeneration, live-cell stains, and automated classification of neurons, astrocytes or microglia using open-source software. Out of 227 compounds with known bioactivities, 29 protected against lipopolysaccha ...[more]

PMID: 38550989

Similar Datasets

Project description:Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 (NFE2L2/Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/?-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/?-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called "star-shaped" cells, harbouring an arsenal of "beneficial" and "harmful" molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, "astrocyte's fil rouge" brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/?-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

Dataset Information

Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.

Publications

Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets