247529 20240403131747.0 10.1186/s40478-022-01500-x doi pmid:36670467 pmid pmc:PMC9854201 pmc DZNE-2023-00206 English 610 Bauer, Susanne 0 Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntington's disease mice. London 2023 Biomed Central article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1711028120_32501 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote LIC: CCBY4 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Cyclin D1 136601-57-5 NLM Chemicals Huntingtin Protein NLM Chemicals Mice MeSH Animals MeSH Huntington Disease: metabolism MeSH Cyclin D1: metabolism MeSH Mice, Inbred C57BL MeSH Interneurons: pathology MeSH Neurons: metabolism MeSH Corpus Striatum MeSH Disease Models, Animal MeSH Mice, Transgenic MeSH Huntingtin Protein: genetics MeSH Huntingtin Protein: metabolism MeSH Chen, Chwen-Yu 1 Jonson, Maria 2 Kaczmarczyk, Lech P:(DE-2719)2810486 3 dzne Magadi, Srivathsa Subramanya 4 Jackson, Walker Scot P:(DE-2719)2810253 5 Last author dzne 10.1186/s40478-022-01500-x Vol. 11, no. 1, p. 17 PERI:(DE-600)2715589-4 1 17 Acta Neuropathologica Communications 11 2023 2051-5960 OpenAccess http://pub.dzne.de/record/247529/files/DZNE-2023-00206.pdf OpenAccess pdfa http://pub.dzne.de/record/247529/files/DZNE-2023-00206.pdf?subformat=pdfa oai:pub.dzne.de:247529 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)2810486 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2810253 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2023 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-10-26 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-10-26 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-10-26 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2022-11-09 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2023-10-26 JCR StatID:(DE-HGF)0100 StatID ACTA NEUROPATHOL COM : 2022 2023-10-26 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2023-05-02T09:09:14Z WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2022-11-09 DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2023-05-02T09:09:14Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-10-26 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-10-26 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID ASC 2023-10-26 Article Processing Charges StatID:(DE-HGF)0561 StatID 2022-11-09 IF >= 5 StatID:(DE-HGF)9905 StatID ACTA NEUROPATHOL COM : 2022 2023-10-26 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2022-11-09 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2023-10-26 Fees StatID:(DE-HGF)0700 StatID 2022-11-09 Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review 2023-05-02T09:09:14Z I:(DE-2719)1013019 AG Jackson Selective Vulnerability of Neurodegenerative Diseases 0 journal VDB UNRESTRICTED I:(DE-2719)1013019 FullTexts