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000247529 037__ $$aDZNE-2023-00206
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000247529 1001_ $$aBauer, Susanne$$b0
000247529 245__ $$aCerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntington's disease mice.
000247529 260__ $$aLondon$$bBiomed Central$$c2023
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000247529 520__ $$aAlthough 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.
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000247529 650_7 $$0136601-57-5$$2NLM Chemicals$$aCyclin D1
000247529 650_7 $$2NLM Chemicals$$aHuntingtin Protein
000247529 650_2 $$2MeSH$$aMice
000247529 650_2 $$2MeSH$$aAnimals
000247529 650_2 $$2MeSH$$aHuntington Disease: metabolism
000247529 650_2 $$2MeSH$$aCyclin D1: metabolism
000247529 650_2 $$2MeSH$$aMice, Inbred C57BL
000247529 650_2 $$2MeSH$$aInterneurons: pathology
000247529 650_2 $$2MeSH$$aNeurons: metabolism
000247529 650_2 $$2MeSH$$aCorpus Striatum
000247529 650_2 $$2MeSH$$aDisease Models, Animal
000247529 650_2 $$2MeSH$$aMice, Transgenic
000247529 650_2 $$2MeSH$$aHuntingtin Protein: genetics
000247529 650_2 $$2MeSH$$aHuntingtin Protein: metabolism
000247529 7001_ $$aChen, Chwen-Yu$$b1
000247529 7001_ $$aJonson, Maria$$b2
000247529 7001_ $$0P:(DE-2719)2810486$$aKaczmarczyk, Lech$$b3$$udzne
000247529 7001_ $$aMagadi, Srivathsa Subramanya$$b4
000247529 7001_ $$0P:(DE-2719)2810253$$aJackson, Walker Scot$$b5$$eLast author$$udzne
000247529 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-022-01500-x$$gVol. 11, no. 1, p. 17$$n1$$p17$$tActa Neuropathologica Communications$$v11$$x2051-5960$$y2023
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