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Biomarkers of Neurotoxicity Inform Mechanisms of Vulnerability and Resilience in Dopaminergic Neurons

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Handbook of Neurotoxicity

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Abstract

Vulnerable pathways and associated stress biomarkers characteristic of neurons may be used to identify the chemical triggers for neurodegenerative diseases. For example, the dopaminergic neurons that die in Parkinson’s disease patients have massive axonal arbors and intense energetic demands that leave them vulnerable to inhibition of energy production. Rotenone, 6-hydroxydopamine, and MPTP/MPP+ (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydrodropyridine and its toxic metabolite 1-methyl-4-phenylpyridinium) inhibit mitochondrial energy production and selectively kill these dopaminergic neurons to cause parkinsonism. LUHMES immortalized dopaminergic neurons are particularly vulnerable to inhibition of oxidative energy metabolism, to oxidative stressors such as 6-hydroxydopamine, to inhibition of glutathione regeneration, and to disruption of metal ion metabolism that is required for mitochondrial oxidative energy metabolism. These studies revealed an integral relationship between oxidative stress and free iron and identified Metallothionein 1G (MT1G) as a biomarker gene that responded dynamically to a wide variety of neurotoxicants in LUHMES neurons. In the brain, neurons depend on astrocytes to supply lactate as a source of metabolic energy, glutathione or its precursors to detoxify oxidative threats, and metallothioneins to protect neurons from free metal ions and oxidative threats. Resilience to these threats depends on reciprocal exchange of metal ions between metallothioneins and metal-responsive transcription factor 1 (MTF1 and likely MTF2). This neuronal model and the MT1G biomarker will be used to screen libraries of environmental toxicants to identify candidate causes of neurodegenerative disease. Follow-up studies will clarify which toxicants attack vulnerable pathways and bypass the bodies’ defenses.

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Abbreviations

6HD:

6-Hydroxydopamine

AD:

Alzheimer’s disease

ANLS:

Astrocyte-neuron lactate shuttle

BSO:

Buthionine sulfoximine

DMPS:

3-Dimercapto-1-propanesulfonic acid

ETC:

Mitochondrial electron transport chain

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

HTS:

High-throughput screening

LUHMES:

Lund human mesencephalic neuronal cells

MAP:

4-(Methylamino)phenol hemisulfate

MPP+:

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydrodropyridine

MT:

Metallothionein

MT1G:

Metallothionein 1G

MTF1:

Metal-responsive transcription factor 1

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SH-SY5Y:

Human neuroblastoma cell line

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Acknowledgments

This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences and the National Institute for Environmental and Health Sciences, National Institutes of Health.

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Authors and Affiliations

  1. Division of Preclinical Innovation, National Institutes of Health, National Center for Advancing Translational Sciences, Bethesda, MD, USA

    David Gerhold, Hyun Hee Kim & Zhi-Bin Tong

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  1. David Gerhold
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  2. Hyun Hee Kim
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  3. Zhi-Bin Tong
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Correspondence to David Gerhold .

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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Gerhold, D., Kim, H.H., Tong, ZB. (2022). Biomarkers of Neurotoxicity Inform Mechanisms of Vulnerability and Resilience in Dopaminergic Neurons. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_183

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