Glutamate excitotoxicity has emerged as a favorite theory for the damage that motor neurons undergo in amyotrophic lateral sclerosis (ALS). Unless glia mop up used glutamate, it accumulates in the synapse and poisons neurons by inducing over-firing and calcium influx. Two recent papers add more fuel to the fire. Writing in the Acta Neuropathologica online April 7, researchers from the University of Tokyo, Japan, report that editing of the RNA for a glutamate receptor component is intimately linked with TDP-43 inclusions, a hallmark of sporadic ALS. And in the April 14 Journal of Neuroscience, scientists from the University of Rome, Italy, show that the non-protein amino acid BMAA acts as a glutamate receptor agonist, potentially causing symptoms of Parkinson disease as well as ALS.

First author Hitoshi Aizawa and senior author Shin Kwak led the Tokyo group. Kwak and colleagues previously showed that the enzyme “adenosine deaminase acting on RNA 2” (ADAR2) edits RNA for the glutamate receptor subunit Glu2R, a component of calcium-dependent AMPA receptors (see ARF related news story on Kawahara et al., 2004; Kwak et al., 2008). ADAR2 catalyzes an adenosine-to-inosine switch essential to produce functional Glu2R, but this editing is incomplete in the motor neurons of people with sporadic ALS (Kawahara et al., 2004). Without properly edited GluR2, AMPA receptors are more permeable to calcium ions, disrupting membrane polarization and causing excitotoxicity. RNA regulation has also been linked to the genetics of familial ALS. Mutations in genes that encode TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS)—proteins that are responsible for RNA editing and trafficking—can cause disease (see ARF related news story on Kwiatkowski et al., 2009 and Vance et al., 2009).

Kwak and coauthors noted that ADAR2 is absent from spinal motor neurons in ALS. Since TDP-43 leaves its normal nuclear localization to form inclusions in the cytoplasm in many ALS cases as well, they tried to find a connection between these two events. The researchers stained spinal cord sections from people who had died of ALS for both ADAR2 and TDP-43. They found that all motor neurons contain ADAR2 in non-ALS, control tissue samples, but many motor neurons lacked the enzyme in ALS sections. The ADAR2-free cells—which presumably had unedited glutamate receptors—uniformly had TDP-43 inclusions in the cytoplasm, outside of the nucleus.

Because the loss of ADAR2 and TDP-43 inclusion formation coincide, the authors conclude that one likely causes the other, although they are not sure which comes first. “Because both deficiency of ADAR2 and TDP-43 knockout induces neuronal death, it would be more reasonable to consider that either one of the two ALS-associated abnormalities induces neuronal death via inducing the other, rather than to consider that these two ALS-associated abnormalities occur simultaneously as a result of other upstream abnormalities,” Kwak wrote in an e-mail to ARF. He plans to investigate the link between ADAR2 and TDP-43 in future studies.

The Rome-based scientists performed electrophysiology experiments to examine the effects of BMAA on neurons. The ingestion of BMAA has been linked, although tenuously, to a unique ALS syndrome among the Chamorro people of Guam (see ARF related news story on Cox et al., 2003). This Guamian ALS includes a mixture of symptoms of ALS, Parkinson disease, and Alzheimer disease.

BMAA is a glutamate receptor agonist, but little is known about its precise mechanism of action. First author Maria Letizia Cucchiaroni and joint senior authors Ezia Guatteo and Nicola Mercuri sought to understand BMAA’s effect on dopaminergic neurons from the substantia nigra of rats to see if the effects could be linked to Parkinson-like symptoms.

The researchers applied BMAA to rat brain slices, and saw that it caused increased calcium influx, with intracellular calcium concentrations nearly tripling upon BMAA treatment. This led to membrane depolarization and toxicity, with cell shrinkage and production of reactive oxygen species. To determine which parts of glutamate receptors BMAA affects, the scientists added antagonists specific for glutamate receptors subunits. They found a GluR1 antagonist blocked the toxic effects of BMAA, suggesting the amino acid binds this receptor subunit. TRPC, or transient receptor potential-like channels containing GluR1 were mostly responsible for BMAA-induced cytotoxicity, with AMPA receptors making a small, non-calcium-dependent contribution as well.

Because Guamian ALS includes parkinsonism, GluR1 excitotoxicity is worth pursuing as a mechanism for typical Parkinson’s, too, Mercuri wrote in an e-mail to ARF. The authors suggest that exposure to BMAA—now known to exist worldwide, not just in Guam—might contribute to idiopathic Parkinson disease.—Amber Dance.

References:
Aizawa H, Sawada J, Hideyama T, Yamashita T, Katayama T, Hasebe N, Kimura T, Yahara O, Kwak S. TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathol. 2010 Apr 7. Abstract

Cucchiaroni ML, Viscomi MT, Bernardi G, Molinari M, Guatteo E, Mercuri NB. Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010 Apr 14;30(15):5176-5188. Abstract

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  1. Amber Dance has nicely summarized both papers. Concerning the Cucchiaroni paper, I believe it is a very important contribution to the literature. Deborah Mash, John Pablo, and colleagues have recently confirmed prior studies by Paul Cox and colleagues that BMAA is accumulated in the brains of patients with Alzheimer disease. They also showed that BMAA is accumulated in the brains of patients with amyotrophic lateral sclerosis, but not in brains of control patients or those with Huntington disease. They have obtained preliminary evidence that BMAA is accumulated in the brains of patients with Parkinson disease.

    The concentration of BMAA in the protein-bound fraction of the brains of Chamorros with ALS/PDC is of the order of 5 mM, while that in the brains of patients with AD, PD, and ALS is approaching 1 mM. However, Cox and colleagues found that the concentration of BMAA in the soluble fraction of the brains of Chamorros with ALS/PDC was about 50 micromolar.

    The paper by Cucchiaroni et al. demonstrates a significant physiological effect of BMAA on dopaminergic neurons. It suggests that a major source of this effect is via the GluR1 subunit and provides a vital link in the pathway from the environmental neurotoxin—BMAA derived from ubiquitous cyanobacteria—to the human diseases AD, PD, and ALS. However, it should be noted that the concentrations used in the study were in the mM range; more chronic, lower-dose studies are needed to simulate the apparent state in humans.

    The field of cyanobacterial BMAA and its role in human neurodegenerative diseases was recently reviewed in a supplement to the journal ALS.

    See also:

    Bradley, W.G., Cox, P.A. Supplement 2. Amyotrophic Lateral Sclerosis. June 2009;10:1-128.

    References:

    . Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol Scand. 2009 Oct;120(4):216-25. PubMed.

    . Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand. 2004 Oct;110(4):267-9. PubMed.

    . A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12228-31. PubMed.

References

News Citations

  1. ALS—An RNA Editing Disease?
  2. New Gene for ALS: RNA Regulation May Be Common Culprit
  3. Dietary Toxins and Neurodegenerative Diseases—Guam Revisited

Paper Citations

  1. . Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004 Feb 26;427(6977):801. PubMed.
  2. . Newly identified ADAR-mediated A-to-I editing positions as a tool for ALS research. RNA Biol. 2008 Oct-Dec;5(4):193-7. PubMed.
  3. . Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205-8. PubMed.
  4. . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11. PubMed.
  5. . Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13380-3. PubMed.
  6. . TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathol. 2010 Jul;120(1):75-84. PubMed.
  7. . Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010 Apr 14;30(15):5176-88. PubMed.

Further Reading

Papers

  1. . Parkinson-dementia complex and development of a new stable isotope dilution assay for BMAA detection in tissue. Toxicol Appl Pharmacol. 2009 Oct 15;240(2):180-8. PubMed.
  2. . Calcium-permeable AMPA receptors containing Q/R-unedited GluR2 direct human neural progenitor cell differentiation to neurons. FASEB J. 2008 Aug;22(8):2888-900. PubMed.
  3. . TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathol. 2010 Jul;120(1):75-84. PubMed.
  4. . Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010 Apr 14;30(15):5176-88. PubMed.
  5. . Selective death of cholinergic neurons induced by beta-methylamino-L-alanine. Neuroreport. 2010 Jan 6;21(1):55-8. PubMed.
  6. . beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-). Exp Neurol. 2009 Jun;217(2):429-33. PubMed.
  7. . Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J Mol Med (Berl). 2005 Feb;83(2):110-20. PubMed.

Primary Papers

  1. . TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathol. 2010 Jul;120(1):75-84. PubMed.
  2. . Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci. 2010 Apr 14;30(15):5176-88. PubMed.