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@ARTICLE{Bauer:247529,
author = {Bauer, Susanne and Chen, Chwen-Yu and Jonson, Maria and
Kaczmarczyk, Lech and Magadi, Srivathsa Subramanya and
Jackson, Walker Scot},
title = {{C}erebellar granule neurons induce {C}yclin {D}1 before
the onset of motor symptoms in {H}untington's disease mice.},
journal = {Acta Neuropathologica Communications},
volume = {11},
number = {1},
issn = {2051-5960},
address = {London},
publisher = {Biomed Central},
reportid = {DZNE-2023-00206},
pages = {17},
year = {2023},
note = {LIC: CCBY4},
abstract = {Although Huntington's disease (HD) is classically defined
by the selective vulnerability of striatal projection
neurons, there is increasing evidence that cerebellar
degeneration modulates clinical symptoms. However, little is
known about cell type-specific responses of cerebellar
neurons in HD. To dissect early disease mechanisms in the
cerebellum and cerebrum, we analyzed translatomes of
neuronal cell types from both regions in a new HD mouse
model. For this, HdhQ200 knock-in mice were backcrossed with
the calm 129S4 strain, to constrain experimental noise
caused by variable hyperactivity of mice in a C57BL/6
background. Behavioral and neuropathological
characterization showed that these S4-HdhQ200 mice had very
mild behavioral abnormalities starting around 12 months of
age that remained mild up to 18 months. By 9 months, we
observed abundant Huntingtin-positive neuronal intranuclear
inclusions (NIIs) in the striatum and cerebellum. The
translatome analysis of GABAergic cells of the cerebrum
further confirmed changes typical of HD-induced striatal
pathology. Surprisingly, we observed the strongest response
with 626 differentially expressed genes in glutamatergic
neurons of the cerebellum, a population consisting primarily
of granule cells, commonly considered disease resistant. Our
findings suggest vesicular fusion and exocytosis, as well as
differentiation-related pathways are affected in these
neurons. Furthermore, increased expression of cyclin D1
(Ccnd1) in the granular layer and upregulated expression of
polycomb group complex protein genes and cell cycle
regulators Cbx2, Cbx4 and Cbx8 point to a putative role of
aberrant cell cycle regulation in cerebellar granule cells
in early disease.},
keywords = {Mice / Animals / Huntington Disease: metabolism / Cyclin
D1: metabolism / Mice, Inbred C57BL / Interneurons:
pathology / Neurons: metabolism / Corpus Striatum / Disease
Models, Animal / Mice, Transgenic / Huntingtin Protein:
genetics / Huntingtin Protein: metabolism / Cyclin D1 (NLM
Chemicals) / Huntingtin Protein (NLM Chemicals)},
cin = {AG Jackson},
ddc = {610},
cid = {I:(DE-2719)1013019},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36670467},
pmc = {pmc:PMC9854201},
doi = {10.1186/s40478-022-01500-x},
url = {https://pub.dzne.de/record/247529},
}