Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific.
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;65:50-61.
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Anne H P
AH
Jansen
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Maurik
M
van Hal
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Ilse C
IC
Op den Kelder
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Romy T
RT
Meier
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Anna-Aster
AA
de Ruiter
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Menno H
MH
Schut
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Donna L
DL
Smith
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, 9713, The Netherlands.
Corien
C
Grit
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, 9713, The Netherlands.
Nieske
N
Brouwer
Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
Willem
W
Kamphuis
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, 9713, The Netherlands.
H W G M
HW
Boddeke
Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, AV, 9713, The Netherlands.
Wilfred F A
WF
den Dunnen
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Willeke M C
WM
van Roon
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Gillian P
GP
Bates
Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.|Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.|Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands.
Elly M
EM
Hol
Department of Cell biology & Histology, Academic Medical Center, Amsterdam, The Netherlands.
Eric A
EA
Reits
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000071058:Huntingtin Protein / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism
D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
Huntington's disease; astrocytes; inclusions; microglia; neurons; oligodendrocytes