c-Jun N-terminal Kinase Mediates Ligand-independent p75NTR Signaling in Mesencephalic Cells Subjected to Oxidative Stress

Kraemer, Bradley R.; Clements, Rachel T.; Escobedo, Cassandra; Nelson, Kendall; Waugh, Carter; Elliott, Andrew; Hall, Wesley C; Schemanski, Montana

doi:10.1016/j.neuroscience.2020.11.036

Cited by 5 publications

(4 citation statements)

References 105 publications

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“…Upon differentiation, LUHMES cells become postmitotic, adopt a gene expression profile characteristic of mature dopaminergic neurons, and develop a neuronal morphology with neurites that extend up to 500 μm in length ( Fig. 1 A ; Lotharius et al, 2005 ; Scholz et al, 2011 ; Kraemer et al, 2021 ). Because of the superior optical qualities of glass compared with plastic, the cultures were established on glass slides containing eight media chambers.…”

Section: Resultsmentioning

confidence: 99%

“…Use of this model system to study neurite degeneration has several advantages. The cells develop neurites that are well-networked and typically >500 μm in length, and the cultures are susceptible to neurodegeneration induced by classic, neurotoxin models of PD such as 6-OHDA, 1-methyl-4-phenylpyridinium ion (MPP+), and rotenone ( Lotharius et al, 2005 ; Zhang et al, 2014 ; Smirnova et al, 2016 ; Kraemer et al, 2021 ). Furthermore, the human origin of LUHMES cells increases the translatability of findings associated with the model, and the conditional immortalization facilitates rapid generation and propagation of cultures ( Scholz et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson’s Disease

Clements

Fuller

Kraemer

et al. 2022

eNeuro

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Neurite degeneration is associated with early stages of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. One method that is commonly used to analyze neurite degeneration involves calculation of a Degeneration Index (DI) following utilization of the Analyze Particles tool of ImageJ to detect neurite fragments in micrographs of cultured cells. However, DI analyses are prone to several types of measurement error, can be time consuming to perform, and are limited in application. Here, we describe an improved method for performing DI analyses. Accuracy of measurements was enhanced through modification of selection criteria for detecting neurite fragments, removal of image artifacts and non-neurite materials from images, and optimization of image contrast. Such enhancements were implemented into an ImageJ macro that enables rapid and fully automated DI analysis of multiple images. The macro features operations for automated removal of cell bodies from micrographs, thus expanding the application of DI analyses to use in experiments involving dissociated cultures. We present experimental findings supporting that, compared to the conventional method, the enhanced analysis method yields measurements with increased accuracy and requires significantly less time to perform. Furthermore, we demonstrate the utility of the method to investigate neurite degeneration in a cell culture model of PD by conducting an experiment revealing the effects of c-Jun N-terminal Kinase on neurite degeneration induced by oxidative stress in human mesencephalic cells. This improved analysis method may be used to gain novel insight into factors underlying neurite degeneration and the progression of neurodegenerative disorders. Significance StatementNeurite degeneration is a cellular event associated with the early stages of multiple types of neurodegenerative disorders. Molecular factors that regulate neurite degeneration remain poorly understood, and existing methods for studying neurite degeneration have limited application and efficiency. Here, we identify modifications to a widely used procedure for analyzing neurite degeneration that reduce measurement error. Such methodological enhancements were incorporated into an ImageJ macro, thereby facilitating rapid and completely automated analysis 2 of neurite degeneration using large sets of micrographs. Using a cell culture model of Parkinson's disease, we demonstrate that the macro facilitates more accurate and efficient neurite degeneration measurements while expanding the suitability of the analysis method for experiments involving dissociated cultures.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson’s Disease

Clements

Fuller

Kraemer

et al. 2022

eNeuro

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“…NOX‐derived ROS has been shown to be necessary for Aβ‐induced p75 NTR ‐mediated apoptosis of two different differentiated neuronal cell lines (Perini et al., 2002; Tsukamoto et al., 2003). Proteolytic cleavage of p75 NTR and JNK activity was increased and required for apoptosis of dopaminergic neurons (induced from a human mesencephalic stem cell line) resulting from exposure to the neurotoxic 6 hydroxydopamine or a lipid peroxidation product, 4‐hydroxynonenal (HNE; Kraemer et al., 2021). HNE can also induce sympathetic neuron apoptosis and neurite degeneration, with neurons derived from p75 NTR ‐deficient mice being resistant (Kraemer et al., 2014).…”

Section: P75ntr Signalling During Conditions Of Environmental Insultmentioning

confidence: 99%

“…However, as highlighted above in situations of environmental stress (such as following ROS‐inducing treatments highlighted in Section 3.6), cleavage of p75 NTR has regularly been observed and, when tested, has been shown to be required for death signalling (e.g., Matusica et al, 2016). Furthermore, oxidative conditions that induce lipid peroxidation stimulates proteolytic cleavage of p75 NTR by increasing the expression of both α‐ and γ‐secretases (Salminen et al., 2017), resulting in pathological cell death signalling (Kraemer et al., 2014, 2021). Specifically relating to hypoxia, p75 NTR has also been reported to be an oxygen‐dependent substrate of γ‐secretase, with hypoxia inducing the increased accumulation of p75CTF and p75ICD (Le Moan et al., 2011).…”

Section: P75ntr Cleavage and Activation During Hypoxia And Oxidative Stressmentioning

confidence: 99%

Is there a role for the p75 neurotrophin receptor in mediating degeneration during oxidative stress and after hypoxia?

Sankorrakul

Qian

Thangnipon

et al. 2021

Journal of Neurochemistry

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Cholinergic basal forebrain (cBF) neurons are particularly vulnerable to degeneration following trauma and in neurodegenerative conditions. One reason for this is their characteristic expression of the p75 neurotrophin receptor (p75NTR), which is up‐regulated and mediates neuronal death in a range of neurological and neurodegenerative conditions, including dementia, stroke and ischaemia. The signalling pathway by which p75NTR signals cell death is incompletely characterised, but typically involves activation by neurotrophic ligands and signalling through c‐Jun kinase, resulting in caspase activation via mitochondrial apoptotic signalling pathways. Less well appreciated is the link between conditions of oxidative stress and p75NTR death signalling. Here, we review the literature describing what is currently known regarding p75NTR death signalling in environments of oxidative stress and hypoxia to highlight the overlap in signalling pathways and the implications for p75NTR signalling in cBF neurons. We propose that there is a causal relationship and define key questions to test this assertion.

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Receptors | Neurotrophin Receptor Signaling

Kraemer

Carter

2021

Encyclopedia of Biological Chemistry III

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c-Jun N-terminal Kinase Mediates Ligand-independent p75NTR Signaling in Mesencephalic Cells Subjected to Oxidative Stress

Cited by 5 publications

References 105 publications

Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson’s Disease

Quantification of Neurite Degeneration with Enhanced Accuracy and Efficiency in an In Vitro Model of Parkinson’s Disease

Is there a role for the p75 neurotrophin receptor in mediating degeneration during oxidative stress and after hypoxia?

Receptors | Neurotrophin Receptor Signaling

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