Huntington's Disease Biomarkers: CAP1 and CAPZB Offer Early‑Stage Tracking
Why biomarkers matter in Huntington's disease
When it comes to testing new therapies for Huntington's disease (HD), researchers need a reliable scoreboard. Without measurable signals from inside the body, a drug trial is a shot in the dark—researchers can give a medication, but they have no clear way to know whether it is slowing the disease, causing hidden damage, or doing nothing at all. That’s why Huntington's disease biomarkers have become a cornerstone of modern trial design.
For years, neurofilament light chain (NfL) has held the spotlight. Elevated NfL in blood or cerebrospinal fluid reliably flags neuronal damage, and its levels rise as HD progresses. However, NfL only tells part of the story; it spikes relatively late, after substantial brain injury has begun. Clinicians and drug developers are therefore hunting for additional markers that light up earlier, capture different biological pathways, and together paint a fuller picture of disease activity.
Early‑stage markers are especially valuable because many experimental treatments aim to intervene before patients develop motor or cognitive symptoms. In that window, the brain may still be salvageable, and an accurate biomarker can verify that a therapy is hitting its intended target.
CAP1 and CAPZB: New candidates from a proteomic survey
A team of scientists based in Cyprus set out to cast a wider net. Instead of zeroing in on a handful of pre‑selected proteins, they performed an untargeted proteomic analysis on serial blood samples from individuals carrying the HD gene mutation. By quantifying every detectable protein and tracking how each one shifted over time, the researchers could spot patterns that traditional approaches would miss.
The results were striking. Two proteins—Cyclase‑Associated Protein 1 (CAP1) and the β‑subunit of Capping Protein (CAPZB)—showed consistent, statistically significant changes well before participants reported any clinical signs. CAP1, known for its role in actin cytoskeleton dynamics, appears to reflect early cellular stress in neurons. CAPZB, part of a complex that regulates actin filament growth, may signal subtle alterations in neuronal connectivity.
Because these proteins are detectable in peripheral blood, they could be incorporated into routine monitoring schedules without invasive procedures. Moreover, their early‑stage trajectory complements NfL, offering a two‑pronged approach: CAP1 and CAPZB capture the initial molecular ripple, while NfL flags downstream neuronal injury.
Validation will be the next hurdle. Independent cohorts, larger sample sizes, and cross‑platform testing (e.g., ELISA versus mass spectrometry) are needed to confirm that the observed changes are robust and reproducible. If the findings hold, clinical trial designers could use CAP1 and CAPZB to stratify participants, set baseline disease activity, and measure therapeutic impact with greater precision.
The Cyprus study also underscores a broader lesson for biomarker discovery: casting a wide net can unearth unexpected candidates. By letting the data speak, rather than forcing a hypothesis onto a limited set of proteins, researchers opened a door to novel biology that might otherwise have stayed hidden.
In the coming years, we can expect a cascade of follow‑up work—longitudinal studies tracking CAP1 and CAPZB in pre‑manifest carriers, investigations into how these proteins interplay with known HD pathways, and, eventually, integration into trial protocols. If successful, they will add two powerful tools to the HD researcher’s arsenal, moving the field a step closer to disease‑modifying therapies that can be measured long before a chorea‑laden gait appears.