The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease

Gabery S, Bergh S, Huridou C, Cheong RY, Baldo B, Scheunemann PG, Schoebel M-L, Holmquist Mengelbier L, Englund E, McLean C, Saft C, Kirik D, Björkqvist M, Halliday G, Petrasch-Parwez E, Nguyen HP, Weber JJ and Petersén Å.

Brain Pathology. 2026;e70088. Published 24 February 2026. doi.org/10.1111/bpa.70088.

Abstract

The pathogenic mechanisms leading to neurodegeneration in Huntington disease (HD) are not fully understood but involve accumulation of toxic mRNA and protein products in the brain. 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-mediated 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-repeat-length-dependent increase in the frequency of SIDT2-immunoreactive intranuclear inclusions. In postmortem tissue of an HD case with Vonsattel grade 0, we demonstrate SIDT2- and mHTT-immunoreactive 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-associated 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-immunoreactive inclusions, while demonstrating the efficacy of overexpressing SIDT2 for lowering detrimental mHTT species. Targeting SIDT2-mediated RNautophagy may offer a potential strategy to ameliorate the molecular pathology in HD.

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