Excitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease

doi:10.1016/j.arcmed.2007.11.011

Archives of Medical Research

Volume 39, Issue 3, April 2008, Pages 265-276

https://doi.org/10.1016/j.arcmed.2007.11.011 Get rights and content

Huntington's disease (HD) is a neurodegenerative hereditary illness originated by the mutation of the gene encoding the huntingtin-protein (htt). Mutated htt (mhtt) is characterized by an increased number of glutamine repeats in the N-terminal end; when 40 or more glutamine residues are present, the disease is manifested. Expression of mhtt leads to the selective death of the medium spiny neurons (MSN) in the neostriatum, resulting in the appearance of generalized involuntary movements, the main phenotypic alteration of HD. The relationship between the expression of mhtt and the death of the MSN is not fully understood. Nonetheless, according to experimental evidence indicating that MSN are selectively vulnerable to the toxicity of glutamate (excitotoxicity) or its analogues, excitotoxic neuronal death is suggested to be involved in neurodegeneration associated with HD. Support for this hypothesis comes from studies in HD postmortem tissue and transgenic mice models, suggesting a correlation between mhtt expression and altered glutamatergic neurotransmission, mainly altered conductance of the N-methyl-d-aspartate (NMDA) glutamate receptor subtype and decreased levels of glutamate transporters. On the other hand, alterations in energy metabolism are well documented in HD patients, which might facilitate excitotoxicity. Throughout this review we will discuss relevant evidence suggesting that altered glutamatergic neurotransmission plays a role in neurodegeneration associated with HD, as well as the possible contribution of deficient energy metabolism to the development of an excitotoxic cell death cascade in MSN. We show data supporting protection by energy substrates against neuronal damage in a rat model combining energy deficit and glutamate toxicity.

Introduction

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that equally affects men and women. HD occurs when the gene of huntingtin protein (htt), located in the 4p16.3 region of the short arm of chromosome 4, shows an increased number of CAG nucleotides 1, 2. Mutant htt (mhtt) contains an elongated N-terminal site characterized by numerous glutamine repeats; when it shows ≥40 glutamine residues the illness is expressed during adulthood. A juvenile form of the disease is observed when the number of glutamine repeats exceeds 60. This is present in 15- to 20-year-old individuals and is characterized by the rapid progression of the illness, the presence of rigidity, seizures, and the accentuated loss of cognitive functions; the death of the patients occurs 7–10 years later (3). HD in adults is characterized by psychiatric disturbances such as irritability, aggressiveness and depression, which precede involuntary motor alterations, the main feature of HD. Progression of motor alterations, also known as choreic movements because of its resemblance to dancing postures, follows three stages. Initially, voluntary movements are accompanied by tremor; progressively, during the second or hyperkinetic phase patients lose their body coordination due to the presence of involuntary abrupt movements (choreic) including the muscles of the limbs, head and trunk, limiting the patient's capacities for daily tasks. A progressive decline in cognitive functions and loss of body weight are also present in this phase. At the final stage, approximately 20 years after its onset, choreic movements are substituted by rigidity and bradykinesia. Death of the patient generally takes place at this stage (4).

The main phenotypic alterations of HD are the consequence of the selective loss of the medium spiny neurons (MSN) in the neostriatum, which include the putamen and the globus pallidus 5, 6. The MSN constitute 95% of the total neuronal population and receive cortical inputs releasing glutamate, the main excitatory neurotransmitter in the mammalian brain. In addition to its role as a neurotransmitter, glutamate can cause the death of neurons through a mechanism known as excitotoxicity (see below). Early studies show that intrastriatal injection of glutamate or some of its analogs such as quinolinic acid and kainic acid induces a similar pattern of neuronal death as described in HD 7, 8, 9. Based on this experimental evidence, excitotoxic neuronal death has been suggested to be involved in the pathogenesis of HD. Supporting this hypothesis, modifications in some of the components of glutamatergic neurotransmission have been reported in postmortem studies of HD patients and transgenic models, suggesting that altered glutamatergic transmission might culminate in the development of an excitotoxic mechanism (see below). However, the relationship between excitotoxicity and expression of mhtt is far from being understood. Diverse experimental paradigms from pharmacological approaches to transgenic models have been used in an attempt to understand the mechanisms leading to MSN degeneration in HD. Throughout this review we will discuss the most relevant evidence supporting the role of excitotoxicity in neurodegeneration associated with HD.

Section snippets

Huntingtin Protein and Transgenic Mouse Models

The htt gene is constituted by 67 exons, and a polymorphic unstable repeated sequence of CAG nucleotides is located in the first exon (10). The product of this gene is a 348 kDa protein ubiquitously expressed throughout the body. The physiological role of htt remains unknown, although it has been related to vesicular transport and to cell transcription (11). The mechanisms underlying the expression of mhtt and the development of the disease are not completely understood. Transgenic mouse models

Glutamatergic Neurotransmission and Excitotoxic Neuronal Death

After its release from synaptic terminals, glutamate activates three different receptor subtypes in postsynaptic neurons: N-methyl-d-aspartate (NMDA) receptors; non-NMDA receptors, sensitive to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid; and metabotropic receptors. Activation of non-NMDA receptors induces the influx of sodium ions and the subsequent depolarization of the plasma membrane, promoting the extrusion of the magnesium ion normally blocking the NMDA

Quinolinic Acid As an Endogenous Excitotoxin in HD

Direct administration of quinolinic acid, an endogenous agonist of NMDA receptors, in the rat striatum causes the death of MSN and reproduces some of the behavioral and biochemical alterations of HD. Quinolinic acid is an endogenous metabolite derived from the kynurenine pathway of tryptophan degradation, and its implication in neuronal death associated with HD has been studied for several years. Postmortem analysis of brains from HD patients at early stages has revealed increased levels of

NMDA Receptors

Functional NMDA receptors are organized in tetrameric structures constituted by the combination of three subunits: NR1, NR2 and NR3. There are four isoforms of the NR2 subunits, NR2A to NR2D, and two of the NR3, NR3A and NR3B. Whereas the binding site of the co-agonist glycine is located in the NR1 subunit, the NR2 subunit contains the glutamate-binding site. A regulatory role has been suggested for the NR3A subunit (25). MSN predominantly affected in HD highly express NR1 and NR2B subunits 26,

Therapies Directed to NMDA Receptor Blockade

The alteration in the NMDA receptors described in HD has led to the suggestion of the potentiality of NMDA receptor antagonists as therapeutic agents for the treatment of HD. To date, diverse clinical trials using NMDA receptor antagonists have been performed in symptomatic HD patients. Preclinical studies show that treatment with the NMDA receptor antagonists amantadine and memantine slow the progression of the illness 48, 49, whereas the NMDA receptor antagonists lamotrigine and ketamine had

Vulnerability of Transgenic Models to NMDA Receptor-mediated Toxicity

Consistent with the hypothesis of enhanced activity of NMDA receptors as a factor involved in the induction of excitotoxicity in HD, in vitro studies have shown that cultured MSN from YAC 72 transgenic mice are more susceptible to glutamate and NMDA mediated excitotoxic death 55, 56. However, in vivo results are controversial. Intrastriatal injection of the NMDA receptor agonist, quinolinic acid, causes extensive neuronal damage in wild-type mice but no neuronal death in the R6 (R6/1 and R6/2)

Kainate and Metabotropic Glutamate Receptors

Despite the vast studies supporting the contribution of NMDA receptors to the pathophysiology of HD, the roles of kainate, AMPA and metabotropic glutamate receptors to neuronal degeneration have received less attention. However, some evidence suggests that alterations in the gene of the GluR6/kainate receptor may be involved in HD. Studies show that a polymorphism of an untranslated region of GluR6/kainate receptor gene is related to onset of the illness 61, 62. Dysfunction in metabotropic

Altered Glutamate Transport in HD

Glutamate transporters keep the extracellular concentration of neurotransmitter at physiological levels; uptake failure induces a slow glutamate clearance promoting glutamate spillover and receptor activation. Severe impairment of glutamate uptake induces amino acid accumulation and receptor overactivation, which in turn will trigger an excitotoxic cell death process if sustained long enough. Alterations in glutamate transporters have been described in neurodegenerative disorders related to

Secondary Excitotoxicity As a Pathogenic Mechanism in HD. Role of Energy Metabolism

Glutamate-mediated neuronal death is highly influenced by the energy state of the cell, and even physiological concentrations of glutamate become toxic during energy failure 77, 78, 79, 80, causing cell death through a process known as secondary excitotoxicity. Under these circumstances cell death results from facilitated NMDA receptor channel opening under depolarizing conditions. NMDA receptor channel is normally blocked by Mg²⁺ ion in a voltage-dependent manner, and this ion is extruded to

Conclusions

The most important evidence suggesting the participation of excitotoxicity in neurodegeneration associated with HD comes from early studies showing that the administration of glutamate receptor agonists into the rat striatum causes the death of MSN. Although a direct relationship between mhtt expression and induction of an excitotoxic process in HD has not been confirmed, recent studies have provided significant evidence relating mhtt expression and altered glutamate neurotransmission.

Acknowledgments

We thank Mrs. Teresa Montiel for technical assistance on figure preparation and experimental procedures. This study was supported by PAPPIT IN213507 (to LM) and CONACYT 194940 fellowship (to AMES).

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Review articleExcitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease

Introduction

Section snippets

Huntingtin Protein and Transgenic Mouse Models

Glutamatergic Neurotransmission and Excitotoxic Neuronal Death

Quinolinic Acid As an Endogenous Excitotoxin in HD

NMDA Receptors

Therapies Directed to NMDA Receptor Blockade

Vulnerability of Transgenic Models to NMDA Receptor-mediated Toxicity

Kainate and Metabotropic Glutamate Receptors

Altered Glutamate Transport in HD

Secondary Excitotoxicity As a Pathogenic Mechanism in HD. Role of Energy Metabolism

Conclusions

Acknowledgments

Life Sci

Life Sci

Neuron

Cell

NeuroRx

Prog Neurobiol

Neurobiol Dis

Exp Neurol

Neurosci Lett

Curr Opin Neurobiol

Prog Neurobiol

Prog Neurobiol

Neurobiol Dis

Neurobiol Aging

Mol Cell Neurosci

Neuron

Neuroscience

Neuron

J Biol Chem

J Biol Chem

Mol Cell Neurosci

Brain Res Bull

Neuroscience

Brain Res

Exp Neurol

Neuropharmacology

Neurosci Lett

Neurobiol Dis

Neurobiol Dis

Exp Neurol

Neuroscience

Brain Res

Neuroscience

Neuroscience

Neuroscience

J Neurol Sci

Cell

A polymorphic DNA marker genetically linked to Huntington's disease

Nature

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

Cell

Huntington's Disease

Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease

Science

Neuropathological classification of Huntington's disease

J Neuropathol Exp Neurol

Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids

Nature

Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat

Somat Cell Mol Genet

Normal huntingtin function: an alternative approach to Huntington's disease

Nat Rev Neurosci

Role of energy metabolism in neuronal death associated with cerebral ischemia and neurodegenerative diseases, and its prevention by energy substrates

Recent Res Dev Neurochem

Strategies for neuroprotection against L-trans-2,4-pyrrolidine dicarboxylate-induced neuronal damage during energy impairment in vitro

J Neurosci Res

Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired

J Neurochem

Hypoxic-ischemic brain injury and oxidative stress

Review article
Excitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease