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MODELING ALS-PDC: ALIGNING BMAA TOXICITY WITH THE BIRTH OF NEURONS INVOLVED IN ALS-PDC AND WITH AGING

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Principal Investigator: Charlton, Clivel G.
Institute Receiving Award Meharry Medical College
Location Nashville, TN
Grant Number R21ES027663
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Sep 2018 to 31 Aug 2021
DESCRIPTION (provided by applicant): Abstract. Amyotrophic Lateral Sclerosis-Parkinson’s Dementia Complex (ALS-PDC) is a severe neurological disorder, caused by degeneration of upper motor glutamine (UMG), nigrostriatal dopamine (NSDA) and basal forebrain acetylcholine (BFbA) neurons. ALS-PDC, locally called Lytico-bodig, occurred with high incidence in Guam. The cause of ALS-PDC is unknown, but several studies indicate that beta-methylamino-L-alanine (BMAA), a non-protein amino acid in food prepared from the cycad plant, is the cause of ALS-PDC. The consumption of BMAA is reduced, so also the incidence of ALS-PDC, which strongly indicate that BMAA is involved in causing ALS- PDC. No study, however, has produced a good model of ALS-PDC, mostly due to the high dosage of BMAA used and the postnatal and acute nature of the exposures. So, studies to determine if BMAA is involved in causing ALS- PDC are critical. This project will test the hypothesis that ALS-PDC is caused by in utero exposures of fetus to BMAA that harms the UMG, NSDA and BFbA neurons during neuronal birth or neurogenesis, a metabolically active and vulnerable period when precursor neurons divide and produce the terminally differentiated phenotypes. BMAA is absorbed from pregnant mothers, who consumed meals containing the amino acid. The toxin reduces the resilience of the neurons, causing them to fail and die ahead of other neurons. This concept suggests that two stages are involved. The 1st is the sensitization or susceptibility stage that occurs when BMAA is absorbed into the fetus from maternal circulation, causing subthreshold damage to the UMG, NSDA and BFbA neurons. The 2nd is the precipitating or inducing stage due to adverse effects of slow metabolic events and the ‘wear and tear’ of aging on the fragile neurons, causing neuronal death later in life. We will test this novel concept via 2 specific aims (SA). SA #1: Pregnant mice will be treated with BMAA to cause subtle fetal neuronal toxicity during gestation day (GD) 8-18, the period of birth/neurogenesis of the fetal UMG, NSDA and BFbA neurons. Behaviors and growth of the offspring will be measured up to 3 months of age, then the animals will be sacrificed and changes in glutamine (Glut), dopamine (DA), acetylcholine (Ach), their metabolites and enzymes (glutaminase, tyrosine hydroxylase, choline acetyltransferase) measured. Cellular staining, immunohistochemistry (IHC), Western blot, etc. will be used to study changes in neurons, mitochondria, TDP-43, alpha-synuclein, amyloid precursor protein, Lewy’s bodies, plaques, tangles and gliosis. SA #2. Study the additive effects of aging on items studied in SA#1 in 6, 12 and 18 months offspring. Binding assays will be employed to determine if BMAA interacts with cytoskeleton (CySk), and Western blot, immunoprecipitation and IHC used to study changes in microtubules, tau, tubulins, kinesins and neurofilaments. Summation: The interaction of BMAA with CySk will be pursued as a mechanism of action for toxic amino acid. BMAA may interact with tubulin, impairing neuronal transporter and spreading the disorder when the ‘BMAA-tubulin’ adduct recycle into other cells. This timed study may reveal the cause for ALS-PDC as well as other idiopathic neurodegenerative disorders.
Science Code(s)/Area of Science(s) Primary: 63 - Neurodegenerative
Publications No publications associated with this grant
Program Officer Jonathan Hollander
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