Amyotrophic lateral sclerosis and excitotoxicity

From pathological mechanism to therapeutic target

E. Bogaert, C. D'Ydewalle, L. van den Bosch

Research output: Contribution to journalArticle

Abstract

Glutamate-induced excitotoxicity is responsible for neuronal death in acute neurological conditions as well as in chronic neurodegeneration. In this review, we give an overview of the contribution of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS). The selective motor neuron death that is the hallmark of this neurodegenerative disease seems to be related to a number of intrinsic characteristics of these neurons. Most of these characteristics relate to calcium entry and calcium handling in the motor neurons as intracellular free calcium concentrations increase quickly due to a high glutamate-induced calcium influx in combination with a low calcium-buffering capacity. The high calcium influx is because of the presence of GluR2 lacking, calcium-permeable AMPA receptors while a low expression of calcium-binding proteins explains the low calcium-buffering capacity. In the absence of these proteins, mitochondria play an important role to remove calcium from the cytoplasm. While all of these characteristics make at least a subpopulation of motor neurons intrinsically very prone to AMPA receptor mediated excitotoxicity, this vulnerability is further increased by the disease process. Mutated genes as well as unknown factors do not only influence the intrinsic characteristics of the motor neurons, but also the properties of the surrounding astrocytes. In conclusion, excitotoxicity remains an intriguing pathological pathway that could not only explain the selectivity of the motor neuron death but also the role of surrounding non-neuronal cells in ALS. In addition, excitotoxicity is also an interesting drug-able target as indicated by the only FDA-approved drug, riluzole, as well as by a number of ongoing clinical trials.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalCNS and Neurological Disorders - Drug Targets
Volume9
Issue number3
StatePublished - 2010
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Calcium
Motor Neurons
AMPA Receptors
Therapeutics
Glutamic Acid
Riluzole
Calcium-Binding Proteins
Astrocytes
Neurodegenerative Diseases
Pharmaceutical Preparations
Mitochondria
Cytoplasm
Clinical Trials
Neurons

Keywords

  • Ampa receptors
  • Astrocytes
  • Ca metabolism
  • Motor neuron
  • Neurodegenerative disease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pharmacology

Cite this

Amyotrophic lateral sclerosis and excitotoxicity : From pathological mechanism to therapeutic target. / Bogaert, E.; D'Ydewalle, C.; van den Bosch, L.

In: CNS and Neurological Disorders - Drug Targets, Vol. 9, No. 3, 2010, p. 297-304.

Research output: Contribution to journalArticle

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