Huntingtin inclusion bodies have distinct immunophenotypes and ubiquitination profiles in the Huntington's disease human cerebral cortex

Swanson, M. E. V.; Tan, A. Y. S.; Tippett, L. J.; Turner, C.; Curtis, M. A.; Scotter, E.; Lashuel, H.; Dragunow, M.; Faull, R. > M.; Murray, H. C.; Singh-Bains, M. K.

doi:10.1101/2025.02.03.636327

bioRxiv · 10.1101/2025.02.03.636327

Huntingtin inclusion bodies have distinct immunophenotypes and ubiquitination profiles in the Huntington's disease human cerebral cortex

Swanson, M. E. V.·Tan, A. Y. S.·Tippett, L. J.·Turner, C.·Curtis, M. A.·Scotter, E.·Lashuel, H.·Dragunow, M.·Faull, R. > M.·Murray, H. C.·Singh-Bains, M. K.

View original source ↗Export metadata ↓

Abstract

Huntingtons disease (HD) is a hereditary neurodegenerative condition caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein. The accumulation of Htt inclusion bodies is a pathological hallmark of HD and a common target for therapeutic strategies. However, the limited efficacy of treatments targeting the Htt protein highlights the need for a better understanding of the role of Htt inclusion bodies in HD pathogenesis. This study examined the heterogeneity of Htt inclusion body composition by co-labelling with three Htt epitope-specific antibodies to characterize Htt inclusion body immunophenotype. We then characterized the size and sub-cellular location of Htt inclusions with distinct immunophenotypes. Using multiplex immunohistochemistry, we also examined the ubiquitination profile of each immunophenotype. Our findings demonstrate that Htt inclusions have a range of immunophenotypes, with some labelled by only one of the three antibodies and others exhibiting co-labelling by several antibodies, thus demonstrating the heterogeneity in inclusion composition and structure. We outline evidence that inclusion bodies exclusively labelled with the EM48 antibody are small, non-nuclear, and more abundant in HD cases with increased CAG repeat length, higher Vonsattel grade, and earlier age of onset. We also find that Htt inclusion bodies labelled by multiple antibodies are more likely to be ubiquitinated, predominantly by K63-rather than K48-linked ubiquitin, suggesting preferential degradation by autophagy. Lastly, we show that ubiquitinated Htt inclusion bodies are more highly immunoreactive for ubiquilin 2 than p62. Our findings highlight the need for multiple antibodies to capture the full spectrum of Htt pathology in HD and imply that future studies should consider the diversity of inclusion body composition and structure when correlating pathology formation to neurodegeneration, clinical symptoms, or disease severity.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Swanson, M. E. V., Tan, A. Y. S., Tippett, L. J., Turner, C., Curtis, M. A., Scotter, E., Lashuel, H., Dragunow, M., Faull, R. > M., Murray, H. C., Singh-Bains, M. K.. 2025-02-03. Huntingtin inclusion bodies have distinct immunophenotypes and ubiquitination profiles in the Huntington's disease human cerebral cortex. https://doi.org/10.1101/2025.02.03.636327

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗

bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗