Amyotrophic Lateral Sclerosis (ALS) is a progressive, degenerative and fatal neurological disorder which involves decreased skeletal muscle function as a result of loss of upper and/or lower motor neurons. Clinical signs of ALS include skeleta muscle weakness, muscle cramping and fatiguing, slurred speech and difficulty swallowing. ALS typically presents later in ife. Cellular degeneration in ALS occurs specifically in the nervous system. Two forms of ALS have been identified. The vasi majority of cases of ALS are referred to as sporadic (SALS), in which the etiology of the disease is unknown, but there is no family history of ALS. Between 5-12% of ALS cases are referred to as Familial ALS (FALS). Some of these appear to be due to a number of identified, inherited mutations in superoxide dismutase-1 (SOD1) the gene which encodes Cu/Zn containing SOD. How ALS causes motor neuron degeneration is as yet unknown, although several postulated mechanisms are thought to contribute to ALS. One major hypothesized mechanism is glutamate mediated excitotoxicity, perhaps due :o impaired astrocytic uptake of glutamate. Following excitotoxicity, elevations of intracellular [Ca] ([Ca]|) with subsequent mitochondrial damage and generation of reactive oxygen species occur; all of these could contribute to motor neuron degeneration. Contribution of environmental exposure factors to the etiology of ALS has been repeatedly hypothesized, bul no specific environmental exposure factors have definitively been linked with ALS. Among the environmental toxicants )roposed as possible contributors to the etiology of ALS include neurotoxic heavy-metals, particularly Hg2+, Pb2* and Cd2* This R21 proposal is designed to test the hypothesis that exposure of motor neurons to methylmercury (MeHg)-predisposes them to excitotoxic damage. In a number of types of neurons, MeHg increases [Ca];, disrupts mitochondrial function,, and causes release of vesicular glutamate from nerve endings. Any of these actions could contribute to enhanced sensitivity of motor neurons to subsequent environmental exposure damage, or in motor neurons having as yet undetermined genetic predisposition to ALS. A transgenic mouse line overexpressing the human mutant SOD1 (G93A) will be used to compare fleets of MeHg in a commonly accepted animal model of FALS. Proposed studies will involve fluorescent measurements of changes in [Ca]h glutamate release and mitochondrial Ca2+ in hypoglossal motor neurons in slices of brainstem of SOD1 mice following chronic MeHg exposure postnatally. The ability of MeHg to exacerbate the onset of ALS-signs will be examined using a rotarod test to determine if the onset of ALS-like phenotype is faster with MeHg. Results of the proposed exploratory study should provide evidence for or against environmental exposure to MeHg as a. possible contributor to motor neuron degeneration during ALS-particularly in susceptible or genetically predisposed populations. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES014357-02
Application #
7270114
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2006-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$183,276
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Ramanathan, Gunasekaran; Atchison, William D (2011) Ca2+ entry pathways in mouse spinal motor neurons in culture following in vitro exposure to methylmercury. Neurotoxicology 32:742-50
Johnson, Frank O; Yuan, Yukun; Hajela, Ravindra K et al. (2011) Exposure to an environmental neurotoxicant hastens the onset of amyotrophic lateral sclerosis-like phenotype in human Cu2+/Zn2+ superoxide dismutase 1 G93A mice: glutamate-mediated excitotoxicity. J Pharmacol Exp Ther 338:518-27
Johnson, Frank O; Atchison, William D (2009) The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology 30:761-5
Limke, Tobi L; Atchison, William D (2009) Application of single-cell microfluorimetry to neurotoxicology assays. Curr Protoc Toxicol Chapter 12:Unit 12.15