Astrocyte molecular signatures during Huntington's disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

The Khakh laboratory used gfaABC1D-RiboTag AAVs to purify and sequence astrocyte actively translated mRNAs from Huntington's disease mouse models at several stages of the disease. Two weeks after AAV injection, striata were homogenized and RNA was purified from (i) cleared lysate as the input and control, and (ii) astrocyte-specific ribosome-associated RNA precipitated via a hemagglutinin (HA) tag. R6/2 mice are a fast developing model of Huntington's disease. Striatal cells show mutant HTT inclusions as early as 4 weeks of age. These mice show the first motor and cognitive symptoms around that age, but they become more evident around 8 week old and progressively impair until the mouse death that occurs around 13 weeks of age. Motor symptoms include increased paw clasping and grooming, impaired grip strength and rotarod performance, gait alterations, involuntary movements, etc. Cognitive impairment includes defects in learning and memory. NCAR mice are the healthy "non-carrier" controls for R6/2. They don't have unexpected phenotypes. Overall design: Q175 transcriptomes were compared to WT at 2, 6 and 12 month old. R6/2 transcriptomes were compared to NCAR at 1, 2 and 3 month old.