Evidence for glutamate excitotoxicity that occurs before the onset of cell loss and motor symptoms in an ovine Huntington's Disease model.
Year: 2023
Type: article
Abstract: Background 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 a triad of 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. OVT73 captures an early prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. Methods 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. Results We have identified transcriptional upregulation from genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in OVT73 medium spiny neurons, the cell type preferentially lost early in the disease. This observation supports the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade initiating process. Moreover, the downstream consequences of excitotoxicity including a downregulation of transcription of components for the oxidative phosphorylation complexes was also observed. We also found that pathways that have been proposed to act to reduce excitotoxicity including the activity of the CREB family of transcription factors (CREB1, ATF2, ATF4 and ATF7) were transcriptionally downregulated. Conclusions To our knowledge, the OVT73 model is the very first large mammalian HD model that exhibits transcriptomic signatures of an excitotoxic process that occurs in the absence of cell loss. Our results indicate that glutamate excitotoxicity is a disease initiating process. Addressing this biochemical defect early may prevent any cell loss and avoid the more complex secondary consequential challenges due to cell death.
Authors: Jiang, Andrew, Lehnert, Klaus, You, Linya, Hawkins, Victoria, Reid, Suzanne, Handley, Renee, Jacobsen, Jessie, Patassini, Stefano, Rudiger, Skye, Mclaughlan, Clive, Kelly, Jennifer, Verma, Paul, Bawden, Simon, Gusella, James, MacDonald, Marcy, Waldvogel, Henry, Faull, Richard, Snell, Russell
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4381272820