TY  - JOUR
AU  - Bauer, Susanne
AU  - Chen, Chwen-Yu
AU  - Jonson, Maria
AU  - Kaczmarczyk, Lech
AU  - Magadi, Srivathsa Subramanya
AU  - Jackson, Walker Scot
TI  - Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntington's disease mice.
JO  - Acta Neuropathologica Communications
VL  - 11
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2023-00206
SP  - 17
PY  - 2023
N1  - LIC: CCBY4
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Huntington Disease: metabolism
KW  - Cyclin D1: metabolism
KW  - Mice, Inbred C57BL
KW  - Interneurons: pathology
KW  - Neurons: metabolism
KW  - Corpus Striatum
KW  - Disease Models, Animal
KW  - Mice, Transgenic
KW  - Huntingtin Protein: genetics
KW  - Huntingtin Protein: metabolism
KW  - Cyclin D1 (NLM Chemicals)
KW  - Huntingtin Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36670467
C2  - pmc:PMC9854201
DO  - DOI:10.1186/s40478-022-01500-x
UR  - https://pub.dzne.de/record/247529
ER  -