Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Gabery, Sanaz LU ; Bergh, Sofia LU ; Huridou, Chrisovalantou ; Cheong, Rachel Y. LU ; Baldo, Barbara LU ; Scheunemann, Paul Günther ; Schoebel, Marie Louisa ; Mengelbier, Linda Holmquist LU ; Englund, Elisabet LU orcid and McLean, Catriona , et al. (2026) In Brain Pathology
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
in press
subject
keywords
aggregation, huntingtin, huntingtin lowering, inclusions, neuropathology, SIDT2
in
Brain Pathology
publisher
Wiley-Blackwell
external identifiers
  • scopus:105031133958
  • pmid:41736445
ISSN
1015-6305
DOI
10.1111/bpa.70088
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.
id
bc029c82-f1bd-47ef-b830-09928a7d7c13
date added to LUP
2026-04-13 14:39:21
date last changed
2026-07-08 04:12:49
@article{bc029c82-f1bd-47ef-b830-09928a7d7c13,
  abstract     = {{<p>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.</p>}},
  author       = {{Gabery, Sanaz and Bergh, Sofia and Huridou, Chrisovalantou and Cheong, Rachel Y. and Baldo, Barbara and Scheunemann, Paul Günther and Schoebel, Marie Louisa and Mengelbier, Linda Holmquist and Englund, Elisabet and McLean, Catriona and Saft, Carsten and Kirik, Deniz and Björkqvist, Maria and Halliday, Glenda and Petrasch-Parwez, Elisabeth and Nguyen, Huu Phuc and Weber, Jonasz Jeremiasz and Petersén, Åsa}},
  issn         = {{1015-6305}},
  keywords     = {{aggregation; huntingtin; huntingtin lowering; inclusions; neuropathology; SIDT2}},
  language     = {{eng}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Brain Pathology}},
  title        = {{The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease}},
  url          = {{http://dx.doi.org/10.1111/bpa.70088}},
  doi          = {{10.1111/bpa.70088}},
  year         = {{2026}},
}