Mechanisms of Toxicity in Huntington's Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

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Tufekci M. A. , Tunali N.

TURKIYE KLINIKLERI TIP BILIMLERI DERGISI, vol.32, no.1, pp.201-213, 2012 (Peer-Reviewed Journal) identifier identifier

  • Publication Type: Article / Review
  • Volume: 32 Issue: 1
  • Publication Date: 2012
  • Doi Number: 10.5336/medsci.2010-20459
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.201-213


Huntington's Disease is an autosomal dominant, late onset and fatal disorder characterized by involuntary choreic movements, cognitive dysfunction and psychological disturbances. The causative mutation is the expansion of the GAG repeats in the first exon of the IT-15 gene. Mutant gene expression causes selective death of striatal gamma aminobutyric acid releasing (GABA-ergic) medium size spiny neurons. Changes in the conformation of the mutant huntingtin (htt) protein, proteolysis and ubiquitin-proteasome system (UPS), transcriptional disregulation and excitotoxicity are among the molecular mechanisms of neurodegeneration. Excess amounts of excitatory chemicals continuously stimulate the cells and cause excitotoxic death of vulnerable cells. Glutamate is one of the excitatory neurotransmitters released from basal ganglia. The striatal neuron loss in Huntington's Disease points out that glutamate receptor mediated excitotoxicity may play a role in the pathogenesis. Excitation of N-methyl-D-Aspartate receptors (NMDARs), which belong to ionotrophic glutamate receptors (iGluR), followed by activation of nuclear factor kappa B (NF +/- B) transcription factor result in neuronal death. NMDARs carry polyamine binding sites apart from glutamate binding sites. Since polyamines are in contact with the mutant htt protein, NMDARs and NF +/- B transcription factor, they may play a central role in neurodegeneration observed in Huntington's Disease. Thus, detailed investigation and understanding of the polyamine metabolism in Huntington's Disease will provide new approaches in the treatment of the disease.