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Series GSE269068 Query DataSets for GSE269068
Status Public on Jun 23, 2024
Title Mutant RNA contributes to neuropathology in new mouse models of Huntington’s disease
Organism Mus musculus
Experiment type Expression profiling by array
Summary Huntington’s disease (HD) is a neurodegenerative polyglutamine (polyQ) disease resulting from the expansion of CAG repeats located in the ORF of the huntingtin gene (HTT). The extent to which mutant mRNA-driven disruptions contribute to HD pathogenesis, particularly in comparison to the dominant mechanisms related to the gain-of-function effects of the mutant polyQ protein, is still a subject of debate. To evaluate the contribution of mutant RNA to HD pathogenesis in vivo, we generated two mouse models through knock‐in strategy at the Rosa26 locus. These models expressed distinct variants of human mutant HTT cDNA fragment: a translated variant (HD/100Q model, serving as a reference) and a nontranslated variant (HD/100CAG model). The cohorts of animals were subjected to a broad spectrum of molecular, behavioral and cognitive analysis for 21 months. Behavioral testing revealed a progressive phenotype in both models, with the HD/100Q model exhibiting a more severe phenotype. The rotarod, static rod and open-field tests showed motor deficits in HD/100CAG and HD/100Q model mice during the light phase, while ActiMot indicated hyperkinesis during the dark phase. Both models also exhibited certain striatal transcriptionopathy. In conclusion, we provide in vivo evidence for a contributory role of mutant RNA in HD pathogenesis. The separated effects resulting from the presence of mutant RNA in the HD/100CAG model led to less severe but, to some extent, similar types of impairments (such as increased anxiety) as in the HD/100Q model.
Overall design Transcriptomic analysis was performed on the nCounter system using a Mouse Neuropathology Panel (measuring the expression of 760 neuropathology-related mouse genes and 10 reference genes, nCounter Analysis System FLEX, NanoString Technologies) according to the manufacturer’s instructions (nCounter XT Assay User Manual, July 2016, MAN-10023-11). For the NanoString nCounter XT CodeSet Gene Expression Assay, we used 100 ng of total RNA (per sample) purified from 21-month-old WT, HD/100Q and HD/100 CAG mice (4 animals per group).
Contributor(s) Wozna-Wysocka M, Jazurek-Ciesiolka M, Przybyl L, Wronka D, Misiorek JO, Suszynska-Zajczyk J, Figura G, Ciesiolka A, Sobieszczanska P, Zeller A, Niemira M, Switonski PM
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Submission date Jun 04, 2024
Last update date Jun 24, 2024
Contact name Agnieszka Fiszer
Organization name Institute of Bioorganic Chemistry Polish Academy of Sciences
Department Department of Medical Biotechnology
Street address Noskowskiego Str. 12/14
City Poznan
ZIP/Postal code 61-704
Country Poland
Platforms (1)
GPL34557 NanoString nCounter® Mouse Neuropathology Panels [XT-CSO-MNROP1-12]
Samples (12)
GSM8305828 WT_striatum_neuropathology_male1
GSM8305829 WT_striatum_neuropathology_male2
GSM8305830 WT_striatum_neuropathology_male3
BioProject PRJNA1120048

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Supplementary file Size Download File type/resource
GSE269068_RAW.tar 130.0 Kb (http)(custom) TAR (of RCC)

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