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September 2011

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Intramural papers of the month

By Raluca Dumitru, Ian Thomas, and Angelika Zaremba
September 2011

Rodent model examines Parkinson's progression

Results from a new study by NIEHS Laboratory of Toxicology and Pharmacology researchers suggest that Parkinson's disease (PD) develops from complex gene-environment interactions. The research team made the finding by creating a mouse model that examined how human alpha-synuclein, a gene mutated in some familial and sporadic PD, interacted with low-grade neuroinflammation.

Using this two-hit rodent model, which involved a genetic lesion and an environmental trigger, investigators discovered that microglia-derived oxidative stress bridged neuroinflammation and alpha-synuclein pathogenic alteration in the mediation of its effects. Furthermore, unlike earlier archetypes, this model reproduced several key factors associated with PD, such as the degeneration of dopaminergic neurons and fibers in the nigrostriatal pathway, while also demonstrating synergistic effects of genetic predisposition and environmental exposures in PD development.

As the second most common neurodegenerative disease in the world, extensive knowledge surrounding a possible gene-environment interaction as a mechanism for Parkinson's progression has previously proven elusive. Therefore, this new model may prove to be an invaluable tool for future PD research.

Citation: Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS. ( Exit NIEHS 2011. Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease. Environ Health Perspect 119(6):807-814.

Cadmium induces transcription without calcium mobilization

Scientists from NIEHS revealed a concentration-dependent effect of cadmium on calcium mobilization and gene expression. These findings have important public health implications because cadmium is a persistent environmental toxicant and exposure to it is associated with several human health conditions, such as kidney dysfunction, cancer, respiratory ailments, and birth defects.

Cadmium affects the expression of hundreds of functionally unrelated genes, by activating multiple signal transduction pathways, but it may also influence the gene expression of second messengers, such as calcium.

Researchers used a protein-based calcium sensor, which was stably expressed in HEK293 cells. Low-level cadmium concentrations were sufficient to induce transcription of cadmium-responsive genes, but did not affect calcium mobilization or increase steady-state mRNA levels of calcium-responsive genes. In contrast, exposure to cytotoxic concentrations of cadmium significantly reduced intracellular calcium stores and altered calcium-responsive gene expression.

The scientists concluded that cytotoxic levels of cadmium activate calcium-responsive transcription as a general response to metal-induced intracellular damage and not via a specific mechanism. The research team plans to further examine the effect of cadmium on human health, by studying the molecular mechanisms that regulate cadmium-responsive transcription at environmentally low-levels of concentration.

Citation: Tvermoes BE, Bird GS, Freedman JH.( Exit NIEHS 2011. Cadmium induces transcription independently of intracellular calcium mobilization. PLoS One 6(6):e20542.

CAR mediates the activation of Sult1e1 gene by the garlic extract diallyl sulfide

According to NIEHS researchers, activation of the Sult1e1 gene by the garlic extract (diallyl sulfide) DAS is mediated by the constitutive active/androstane receptor (CAR). This study is the first to show this interaction and may lead to important discoveries in the prevention of stomach, lung, liver, and colon cancer.

CAR (NR1I3), a member of the nuclear receptor superfamily, is usually activated by numerous xenobiotics and endobiotics. It is involved from drug metabolism to energy homeostasis. DAS can positively regulate the production of various enzymes in the liver. When the investigators exposed wild type mice to DAS, Sult1e1 was rapidly induced, but exposure to DAS in mice that lacked CAR led to a small induction of the Sult1e1 gene. Therefore, CAR mediated this interaction.

One other finding in this report is that strong Sult1e1 induction did not affect the endogenous E2 levels in the blood. Further pharmacokinectical, pharmacogenetical, and biochemical studies are necessary to understand this aspect of the research.

Citation: Sueyoshi T, Green WD, Vinal K, Woodrum TS, Moore R, Negishi M.( Exit NIEHS 2011. Garlic extract diallyl sulfide (DAS) activates nuclear receptor CAR to induce the Sult1e1 gene in mouse liver. PLoS One 6(6):e21229.

A novel mechanism that may underlie learning and memory

A recent study conducted by researchers at NIEHS identified a novel mechanism that could have broad implications for neurologic disorders such as Alzheimer's disease and schizophrenia. Previous data support the notion that synaptic plasticity plays a major role in certain forms of learning and memory. This work is the first to show that that timing for the release of acetylcholine, one of the major neurotransmitters in the brain, is critical for the plasticity of synapses, or nerve cell connections.

Long-term potentiation (LTP) and long-term depression (LTD) are two well-studied types of synaptic plasticity. LTP strengthens the synaptic plasticity while LTD reduces it. By electrically stimulating different areas of the cholinergic pathway, the authors found that a very small change in the timing of stimulation and, therefore, acetylcholine release, can alter the type of synaptic plasticity inducing either LTP or LTD.

The researchers also generated mice in which the cholinergic neurons selectively expressed a light-sensitive protein. As a result they were able to selectively activate cholinergic inputs and monitor how the release of acetylcholine affected synaptic plasticity. Using this approach they were able to confirm the results obtained with electrical stimulation and, more importantly, were able to modulate the synaptic strength by either inducing LTP or LTD.

Citation: Gu Z, Yakel JL. ( Exit NIEHS 2011. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71(1):155-165.

(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award fellow in the Stem Cell Biology Group of the Laboratory of Molecular Carcinogenesis. Ian Thomas is a public affairs specialist in the NIEHS Office of Communications and Public Liaison. Angelika Zaremba, Ph.D., is a visiting postdoctoral fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group.)

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