Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model

Hum Mol Genet. 2024 Aug 18;33(17):1524-1539. doi: 10.1093/hmg/ddae087.

Abstract

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

Keywords: Huntington's disease; glutamate excitotoxicity; prodromal; single nuclei RNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Death / genetics
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Disease Models, Animal*
  • Glutamic Acid* / metabolism
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease* / genetics
  • Huntington Disease* / metabolism
  • Huntington Disease* / pathology
  • Medium Spiny Neurons
  • Neurons* / metabolism
  • Neurons* / pathology
  • RNA-Seq
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate* / genetics
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Sheep
  • Transcriptome / genetics

Substances

  • Glutamic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, AMPA
  • Huntingtin Protein
  • Receptors, Kainic Acid