Astro- versus microglia-enriched transcriptomes from aged Atxn2-CAG100-knockin mice suggest underlying pathology of RNA processing at ribosomes, and possibly at U-bodies [panRNAseq]

Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis type 13 (ALS13) are triggered by polyglutamine expansion in Ataxin-2 (ATXN2). To understand these neurodegenerative disorders at the molecular level, the brains of 10-month-old Atxn2-CAG100-knockin mice were analyzed either as a whole or as microglial, astroglial (and neuronal) fractions via global RNA sequencing. Data was validated by comparison with spinal cord oligonucleotide microarray profile. Here, glial fractions showed upregulation of Gpnmb (to 2082%), Cst7, Clec7a, Axl, Csf1, Lgals3, Lgals3bp, Slc11a1, and Usp18 as an unspecific neuroinflammatory signature, versus downregulation of the Nefh (to <19%), Scn4b, Camk2b, Rab15, and Grin1 synaptic mRNAs correlating with circuit disconnection. In all fractions, reductions of Kif5a, Rph3a, and Cplx1 were noted, versus disease-specific inductions of ribosomal subunits, presumably mirroring the partial loss-of-function of ATXN2 as RNA translation modulator. Glial tRNAs were also consistently upregulated. Selective accumulation of embryonic factors Rnu1b2 (8-fold) and Eef1a1 versus downregulation of adult Eef1a2, specify mutation impact on splicing and translation elongation. As a potential underpinning of toxic gain-of-functions, proteostasis factor Rnf213 was increased in all fractions. These transcriptome data suggest altered spliceosome and ribosomal machinery, with massive microgliosis versus mild astrogliosis, at the core of SCA2 and ALS13. The quantity and quality of rRNA and U1 snRNA should be assessed next.