Retinal affectation in Huntington’s disease mouse models concurs with a local innate immune response

Huntington’s disease (HD) is a devastating disorder caused by aberrant expansion of CAG repeats in the HTT gene. Striatal dysfunction has been widely studied in HD mouse models. However, cumulative evidence indicates that the retina can also be functionally altered with consequences for visual function and circadian rhythms. The retina is the most exposed part of the central nervous system that can be used for monitoring the health status of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we linked the retinal alterations with those in the inner brain. We confirmed the malfunction of the R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum, indicating a profound retinal affectation in HD. Tissue-enriched genes were downregulated in both areas, but a neuroinflammation signature was specifically induced in the R6/1 retina due to glial activation that was reminiscent of the situation in HD patient’s brains. These phenomena were confirmed in the zQ175 strain, and were accompanied by a differential impairment of the autophagy system between both tissues. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD. ### Competing Interest Statement The authors have declared no competing interest. * A2m : Alpha-2-macroglobulin Actb : Actin beta Arr3 : arrestin 3 cAMP : cyclic adenosine monophosphate CNS, central nervous system Ctss : Cathepsin S DAPI : 4’-6-diamidino-2-phenylindole DEG, differentially expressed gene ERG, electroretinogram FDR : false discovery rate Gapdh : Glyceraldehyde-3-phosphate dehydrogenase GCL, ganglion cell layer GFAP : glial fibrillary acidic protein Gnat1 : G-Protein subunit alpha transducin 1 H2-K1 : H-2 class I histocompatibility antigen, K-B alpha chain HD, Huntington’s disease Hmox1 : Heme oxygenase 1 HTT, huntingtin Iba-1 : ionized calcium binding adaptor molecule 1 Il1b : interleukin 1b Il6 : interleukin 6 INL : inner nuclear layer IPL, inner plexiform layer IRF : interferon regulator factor KI, knock-in ONL : outer nuclear layer OPL, outer plexiform layer Opn1sw : Opsin 1, short wave sensitive Rho : rhodopsin RNFL : retinal nerve fibre layer RT-qPCR : retrotranscription and quantitative PCR scRNA-seq, single cell RNA sequencing SD-OCT : spectral domain optical coherence tomography STAT, Signal transducer and activator of transcription Tbp : TATA-box binding protein TFBS : transcription factor binding site Tnf : Tumor necrosis factor Trf : Transferrin TUNEL : terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling UHDRS, Unified Huntington’s Disease Rating Scale wt : wild-type