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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies

by
Georg Auburger
1,2,*,†,
Arvind Reddy Kandi
1,†,
Rajkumar Vutukuri
3,
Luis-Enrique Almaguer-Mederos
1,
Suzana Gispert
1,
Nesli-Ece Sen
1 and
Jana Key
1,*
1
Experimental Neurology, Clinic of Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany
2
Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
3
Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2026, 15(8), 699; https://doi.org/10.3390/cells15080699
Submission received: 25 March 2026 / Accepted: 13 April 2026 / Published: 15 April 2026
Versions Notes

Abstract

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 as microglial, astroglial and neuronal fractions via global RNA sequencing. Data were validated by comparison with the spinal cord oligonucleotide microarray profile or filtered by RNA-seq consistency. Here, we show that the mutation causes a massive inflammatory response in microglia and a reciprocal loss of neuronal transcripts in glial fractions, suggesting severe synapse loss. Beyond these general neurodegenerative signs, we identify pathognomonic changes in the machinery for protein translation and RNA splicing. 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 axonal Nefh (to <19%), and synaptic Scn4b, Camk2b, Rab15, and Grin1 mRNAs correlating with circuit disconnection. In all fractions, reductions in 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. Selective accumulations of embryonic factors Rnu1b2 and Eef1a1 versus downregulation of adult Eef1a2 specify the mutation impact on splicing and translation elongation. As a potential underpinning of toxic gain-of-function, the proteostasis transcript Rnf213 appeared increased in astroglial and microglial fractions. These transcriptome data suggest altered ribosomal and spliceosome machinery, with massive microgliosis versus mild astrogliosis, at the core of SCA2 and ALS13.
Keywords: Miltenyi MACS adult brain separator; fractionation controls Aif1, Gfap, Map2, Cldn5; RNA-seq; STRING enrichment bioinformatics; neurofilament loss; mRNA circularization; translation dynamics; uridine-rich small nuclear RNA; U1 3′ stem-loop structure recognition by SMN Miltenyi MACS adult brain separator; fractionation controls Aif1, Gfap, Map2, Cldn5; RNA-seq; STRING enrichment bioinformatics; neurofilament loss; mRNA circularization; translation dynamics; uridine-rich small nuclear RNA; U1 3′ stem-loop structure recognition by SMN

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MDPI and ACS Style

Auburger, G.; Kandi, A.R.; Vutukuri, R.; Almaguer-Mederos, L.-E.; Gispert, S.; Sen, N.-E.; Key, J. Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies. Cells 2026, 15, 699. https://doi.org/10.3390/cells15080699

AMA Style

Auburger G, Kandi AR, Vutukuri R, Almaguer-Mederos L-E, Gispert S, Sen N-E, Key J. Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies. Cells. 2026; 15(8):699. https://doi.org/10.3390/cells15080699

Chicago/Turabian Style

Auburger, Georg, Arvind Reddy Kandi, Rajkumar Vutukuri, Luis-Enrique Almaguer-Mederos, Suzana Gispert, Nesli-Ece Sen, and Jana Key. 2026. "Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies" Cells 15, no. 8: 699. https://doi.org/10.3390/cells15080699

APA Style

Auburger, G., Kandi, A. R., Vutukuri, R., Almaguer-Mederos, L.-E., Gispert, S., Sen, N.-E., & Key, J. (2026). Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies. Cells, 15(8), 699. https://doi.org/10.3390/cells15080699

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