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Glutamate uptake is reduced in prefrontal cortex in Huntington's disease

Bjørnar Hassel1, Shoshi Tessler, Richard L M Faull

  • 1Norwegian Defense Research Establishment, P.O. Box 25, 2027 Kjeller, Norway. bjornar.hassel@ffi.no

Neurochemical Research
|August 30, 2007
PubMed

Insights

Huntington's disease (HD) involves CAG repeat expansion, leading to impaired glutamate uptake in the brain. This dysfunction may contribute to neuronal damage in HD patients.

Area of Science:

  • Neuroscience
  • Genetics
  • Neurodegenerative Diseases

Background:

  • Huntington's disease (HD) is a genetic disorder caused by CAG repeat expansion in the HD gene.
  • The exact mechanisms by which this mutation leads to neuronal dysfunction and degeneration remain unclear.
  • Previous studies in animals with long CAG repeats indicated potential inhibition of glutamate uptake.

Purpose of the Study:

  • To investigate the role of glutamate uptake impairment in the pathophysiology of Huntington's disease.
  • To correlate CAG repeat expansion size with disease severity and glutamate transporter function in HD patients.

Main Methods:

  • Analysis of post-mortem brain tissue from seven HD patients with moderate CAG expansions (40-52 repeats).
  • Measurement of [(3)H]glutamate uptake in the prefrontal cortex.
  • Assessment of synaptic and astrocytic markers, including synaptophysin, AMPA receptors, GFAP, and glutamate transporter EAAT1.
  • Evaluation of the effect of dithiothreitol on glutamate uptake in control and HD brains.

Main Results:

  • A strong correlation was found between CAG repeat expansion size and HD grade at autopsy (r=0.88, p=0.0002).
  • Glutamate uptake was significantly reduced by 43% in the prefrontal cortex of HD patients.
  • Glutamate uptake showed an inverse correlation with CAG repeat expansion (r= -0.82, p=0.015).
  • Synaptic and astrocytic marker levels remained unchanged in HD brains.
  • Dithiothreitol improved glutamate uptake in control brains but not in HD brains, suggesting irreversible oxidation of glutamate transporters.

Conclusions:

  • Impairment of glutamate uptake is a significant finding in Huntington's disease brains with moderate CAG expansions.
  • Reduced glutamate uptake may be due to irreversible oxidation of glutamate transporters.
  • This impairment in glutamate transport function likely contributes to neuronal dysfunction and degeneration observed in Huntington's disease.

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