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  • New Study Links Immune System Proteins to Huntington's Disease Mechanism

    Huntington's disease is a debilitating genetic condition characterized by a progressive decline in movement, mood, and cognition. At its core is a genetic abnormality: an expansion of DNA repeats within the huntingtin gene. These repeats—CAG on one DNA strand and its complementary CTG—can extend to as many as 120 copies, far beyond the typical range of fewer than 40. Such expansions distort the DNA structure, making it prone to breakage and replication errors, which ultimately lead to nerve cell dysfunction and death.

    A study led by Catherine Freudenreich, chair of the biology department at Tufts University, demonstrates how these repeat expansions occur. Published in Proceedings of the National Academy of Sciences, the research identifies a surprising culprit: APOBEC proteins, part of the immune system’s antiviral arsenal.

    APOBEC Proteins and DNA Instability
    Apolipoprotein B mRNA editing catalytic proteins (APOBECs) are known for their role in combating viral infections. These enzymes mutate viral DNA by removing an amine group from cytosine bases, a process called deamination. This tactic renders viral genetic material ineffective, buying time for the adaptive immune system to mount a more targeted response.

    Freudenreich’s team found, however, that APOBECs might inadvertently target the body’s own DNA. DNA sequences prone to forming single-stranded loops—like those within the huntingtin gene—are particularly vulnerable. When APOBEC enzymes deaminate cytosines in these loops, they destabilize the DNA. This increases the error rate during repair, leading to the insertion of additional CAG/CTG repeats. Over time, these expansions disrupt the normal function of the huntingtin gene, contributing to Huntington's disease progression.

    Pinpointing APOBEC's Role
    The researchers studied individual APOBEC proteins in a yeast model to identify those most likely to drive DNA repeat expansions. APOBEC3A emerged as the key player, with a smaller contribution from APOBEC3B. In collaboration with Steve Roberts of the University of Vermont, the team analyzed protein expression data from brain tissue of deceased Huntington’s patients. They found strikingly high levels of APOBEC3A in these samples, far exceeding levels typically observed in other conditions, such as breast cancer where APOBECs are already implicated.
    “This means that APOBECs are in the right place to cause trouble, and that makes them really intriguing candidates for disease initiation,” Freudenreich explained.

    Potential Pathways for Treatment
    The study also hinted at other proteins that might assist APOBECs in triggering repeat expansions, adding complexity to the picture. The team is now investigating whether inhibitors targeting APOBECs could reduce their activity and slow disease progression.
    Additionally, the research raises broader questions about whether viral infections could exacerbate Huntington’s disease. Viral infections often lead to increased APOBEC activity, suggesting a potential environmental trigger for the disease.

    Publication Details
    R.E. Brown, M. Coxon, B. Larsen, M. Allison, A. Chadha, I. Mittelstadt, T.M. Mertz, S.A. Roberts, C.H. Freudenreich, APOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats, Proc. Natl. Acad. Sci. U.S.A.
    122 (2) e2408179122,
    https://doi.org/10.1073/pnas.2408179122 (2025).

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