BMAA selectively injures motor neurons via AMPA/kainate receptor activation

Shyam Rao, Sandra Anne Banack, Paul Alan Cox, John H. Weiss

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations (∼ 30 μM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca2+]i rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.

Original languageEnglish (US)
Pages (from-to)244-252
Number of pages9
JournalExperimental Neurology
Volume201
Issue number1
DOIs
StatePublished - Sep 1 2006

Fingerprint

Kainic Acid Receptors
AMPA Receptors
Motor Neurons
Alanine
Amyotrophic Lateral Sclerosis
Seeds
Plant Structures
Excitatory Amino Acid Antagonists
Poisons
Primates
Reactive Oxygen Species
Spinal Cord
Eating
Phenotype
Neurons
Wounds and Injuries

Keywords

  • ALS
  • ALS-PDC
  • ALS/PDC
  • AMPA
  • Amyotrophic lateral sclerosis
  • Ca
  • Cell culture
  • Cycad
  • Glutamate
  • Guam
  • Motor neuron
  • ROS

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

BMAA selectively injures motor neurons via AMPA/kainate receptor activation. / Rao, Shyam; Banack, Sandra Anne; Cox, Paul Alan; Weiss, John H.

In: Experimental Neurology, Vol. 201, No. 1, 01.09.2006, p. 244-252.

Research output: Contribution to journalArticle

Rao, Shyam ; Banack, Sandra Anne ; Cox, Paul Alan ; Weiss, John H. / BMAA selectively injures motor neurons via AMPA/kainate receptor activation. In: Experimental Neurology. 2006 ; Vol. 201, No. 1. pp. 244-252.
@article{18f4b5f21a9848199669778de9d5ed4b,
title = "BMAA selectively injures motor neurons via AMPA/kainate receptor activation",
abstract = "The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations (∼ 30 μM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca2+]i rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.",
keywords = "ALS, ALS-PDC, ALS/PDC, AMPA, Amyotrophic lateral sclerosis, Ca, Cell culture, Cycad, Glutamate, Guam, Motor neuron, ROS",
author = "Shyam Rao and Banack, {Sandra Anne} and Cox, {Paul Alan} and Weiss, {John H.}",
year = "2006",
month = "9",
day = "1",
doi = "10.1016/j.expneurol.2006.04.017",
language = "English (US)",
volume = "201",
pages = "244--252",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - BMAA selectively injures motor neurons via AMPA/kainate receptor activation

AU - Rao, Shyam

AU - Banack, Sandra Anne

AU - Cox, Paul Alan

AU - Weiss, John H.

PY - 2006/9/1

Y1 - 2006/9/1

N2 - The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations (∼ 30 μM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca2+]i rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.

AB - The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations (∼ 30 μM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca2+]i rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.

KW - ALS

KW - ALS-PDC

KW - ALS/PDC

KW - AMPA

KW - Amyotrophic lateral sclerosis

KW - Ca

KW - Cell culture

KW - Cycad

KW - Glutamate

KW - Guam

KW - Motor neuron

KW - ROS

UR - http://www.scopus.com/inward/record.url?scp=33747191785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33747191785&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2006.04.017

DO - 10.1016/j.expneurol.2006.04.017

M3 - Article

C2 - 16764863

AN - SCOPUS:33747191785

VL - 201

SP - 244

EP - 252

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -