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    Scientists Unveil First Detailed Image of Huntington’s Disease Fibrils

    By University of GroningenNo Comments3 Mins Read
    Visualization of a Clump of Huntington Protein
    Visualization of a clump of dozens of huntingtin protein fragments, showing both the highly ordered core (arrow shapes), but also the dynamic ‘fuzzy coat’ on the surface. The Huntington disease mutation forms the core, but it is the fuzzy coat on the surface that is exposed to the brain cell environment. This fuzzy coat can then engage with cellular components and cause the cells to malfunction. Credit:
    Markus Miettinen, University of Bergen, Norway

    Researchers mapped the unique structure of protein clumps in Huntington’s disease, opening doors to better diagnostics and treatments.

    Huntington’s disease (HD) is a genetic disorder in which nerve cells in specific regions of the brain progressively deteriorate and die. The disease is caused by a mutated form of the huntingtin protein, which leads to the formation of abnormal clumps.

    Patrick van der Wel
    This is Patrick van der Wel, Professor of Solid State NMR Spectroscopy at the University of Groningen, the Netherlands, corresponding author on the Nature Communications paper. Credit: Sylvia Germes

    Unlike other protein-clumping diseases such as Alzheimer’s or Parkinson’s, the exact structure of these huntingtin clumps had remained unknown—until now.

    An international team of scientists, including Professor Patrick van der Wel from the University of Groningen, has combined computational modeling with experimental techniques to reveal the first detailed image of these disease-related clumps. Their research uncovers new insights into the distinctive “fuzzy coat” that covers the surface of these protein aggregates.

    Diagnostics and treatments

    Similar to the clumps in Alzheimer’s and Parkinson’s, the clumps in Huntington’s disease are elongated shapes called fibrils. However, the Huntington’s fibrils differ in important ways from those in other fibril-induced diseases.

    The Structure of Huntington’s Fibrils
    Visualization of the protein clumps associated with Huntington’s disease, determined by combining simulations and multiple complementary types of experiments. The figure shows the overall structure at the top, with aspects of the disordered surface (fuzzy coat, left) and the protected core (right) shown in detail below. This coat is targeted by other proteins in the cell. However, the findings in the study suggest that the fuzzy coat will resist these interactions, which has implications for our understanding of how these toxic proteins can be targeted for destruction. Credit: Adapted from Bagherpoor Helabad, M. et al, Nature Communications.

    ‘Knowing the structure of the protein clump is a critical piece of the puzzle of how these proteins play their role in the disease,’ says Van der Wel. It also paves the way for developing diagnostics and perhaps even treatments. ‘It’s important to monitor the disease proteins in patients, for example during experimental treatments.’ The project was supported by Huntington’s disease foundations, which are largely funded by families of patients and the general public.

    Reference: “Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease” by Mahdi Bagherpoor Helabad, Irina Matlahov, Raj Kumar, Jan O. Daldrop, Greeshma Jain, Markus Weingarth, Patrick C. A. van der Wel and Markus S. Miettinen, 30 December 2024, Nature Communications.
    DOI: 10.1038/s41467-024-55062-8

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