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Recent studies described an unconventional autophagic pathway involving DNA and RNA degradation through DNautophagy and RNautophagy that is regulated by the lysosomal protein SID1 transmembrane family member 2 (SIDT2). Interestingly, SIDT2 has been shown to bind to the expanded CAG repeat in the mutant huntingtin (mHTT) transcript and lower mHTT in vitro. The aim of the present study was to determine whether SIDT2 levels are altered in HD and whether manipulation of SIDT2\u2010mediated RNautophagy can alter HD pathology. We demonstrate a significant reduction of SIDT2 protein levels in the striatum and in the lateral hypothalamic area in postmortem HD brains compared to control cases without effects on SIDT2 mRNA levels. In frontal cortical postmortem HD tissue, we show a CAG\u2010repeat\u2010length\u2010dependent increase in the frequency of SIDT2\u2010immunoreactive intranuclear inclusions. In postmortem tissue of an HD case with Vonsattel grade 0, we demonstrate SIDT2\u2010 and mHTT\u2010immunoreactive inclusions not only in the frontal cortex, but also in the striatum and the lateral hypothalamic area. In the R6\/2 mouse model of HD, we show that SIDT2 inclusions form at later stages than mHTT inclusions. Overexpression of SIDT2 using adeno\u2010associated viral vectors injected into the hypothalamus of R6\/2 mice led to a reduction of mHTT inclusions in the lateral hypothalamic area. Similarly, in a neuronal cell model, overexpression of SIDT2 reduced soluble and insoluble mHTT exon 1 protein levels. Taken together, our results reveal novel pathology in clinical HD cases and in experimental models, characterized by the accumulation of SIDT2\u2010immunoreactive inclusions, while demonstrating the efficacy of overexpressing SIDT2 for lowering detrimental mHTT species. Targeting SIDT2\u2010mediated RNautophagy may offer a potential strategy to ameliorate the molecular pathology in HD.<\/jats:p>","DOI":"10.1111\/bpa.70088","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T03:11:58Z","timestamp":1773025918000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The\n                    <scp>DNA<\/scp>\n                    \/\n                    <scp>RNA<\/scp>\n                    autophagy protein\n                    <scp>SIDT2<\/scp>\n                    as a novel neuropathological hallmark in Huntington disease"],"prefix":"10.1111","volume":"36","author":[{"given":"Sanaz","family":"Gabery","sequence":"first","affiliation":[{"name":"Translational Neuroendocrine Research Unit, Department of Experimental Medical Science Lund University  Lund 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