Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific

Anne H P Jansen, Maurik van Hal, Ilse C Op den Kelder, Romy T Meier, Anna-Aster de Ruiter, Menno H Schut, Donna L Smith, Corien Grit, Nieske Brouwer, W. Kamphuis, H W G M Boddeke, Wilfred F A den Dunnen, Willeke M C van Roon, Gillian P Bates, Elly M Hol, Eric A Reits

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Abstract

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions could be present in all brain cells. The effects of nuclear inclusion formation have been mainly studied in neurons, while the effect on glia has been comparatively disregarded. Astrocytes, microglia, and oligodendrocytes are glial cells that are essential for normal brain function and are implicated in several neurological diseases. Here we examined the number of nuclear mHTT inclusions in both neurons and various types of glia in the two brain areas that are the most affected in HD, frontal cortex, and striatum. We compared nuclear mHTT inclusion body formation in three HD mouse models that express either full-length HTT or an N-terminal exon1 fragment of mHTT, and we observed nuclear inclusions in neurons, astrocytes, oligodendrocytes, and microglia. When studying the frequency of cells with nuclear inclusions in mice, we found that half of the population of neurons contained nuclear inclusions at the disease end stage, whereas the proportion of GFAP-positive astrocytes and oligodendrocytes having a nuclear inclusion was much lower, while microglia hardly showed any nuclear inclusions. Nuclear inclusions were also present in neurons and all studied glial cell types in human patient material. This is the first report to compare nuclear mHTT inclusions in glia and neurons in different HD mouse models and HD patient brains. GLIA 2016.

Original languageEnglish
Pages (from-to)50-61
JournalGLIA
Volume65
DOIs
Publication statusPublished - 02 Jan 2017

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    Jansen, A. H. P., van Hal, M., Op den Kelder, I. C., Meier, R. T., de Ruiter, A-A., Schut, M. H., Smith, D. L., Grit, C., Brouwer, N., Kamphuis, W., Boddeke, H. W. G. M., den Dunnen, W. F. A., van Roon, W. M. C., Bates, G. P., Hol, E. M., & Reits, E. A. (2017). Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific. GLIA, 65, 50-61. https://doi.org/10.1002/glia.23050