Serving Tau up on a Platelet: Identifying a Novel Method to Monitor Huntington’s Disease

Imagine a disease that gradually degrades your ability to control your body movements and emotional state, leading to cognitive decline and the development of mood disorders like depression and anxiety. This dual deterioration of both mental and physical function is the reality faced by people with Huntington's Disease (HD), a rare but devastating genetic disorder.

HD is caused by a mutation that leads to the synthesis of an abnormal form of the protein, huntingtin. Fragments of the protein accumulate in the brain, ultimately disrupting the regions that govern motor function, thinking, and emotion. It typically takes 10 to 30 years for HD to fully progress. Development of tools to effectively monitor the progress of disease is vital to understand HD so that patients can receive ever-improving care.

New findings by an international team of researchers, including Dr. Melanie Alpaugh in the Department of Molecular and Cellular Biology, may help clinicians in this quest.

“If clinicians have better ways to assess HD progression, they are better able to help patients manage the disease,” explains Alpaugh, noting that while the disease cannot be cured, treatment can help manage symptoms. 

Mutations in the huntingtin protein may lie at the heart of the disease, but Alpaugh and colleagues were interested in another protein with potential as a target for monitoring HD: tau.  Tau is an important structural protein in many cells and is known to accumulate in the brain and nervous tissue of patients with a number of other neurodegenerative diseases, including Alzheimer’s and Parkinson’s, as well as HD.

The problem, though, is that assessing tau levels in the spinal fluid is very invasive. Alpaugh and her colleagues wanted to know whether they could detect this important biomarker using a technique that simply requires a blood sample.

“Advances in technology now make it possible to detect low levels of molecular biomarkers that may be found in peripheral tissues like blood,” says Alpaugh.

The researchers focussed on two components in the blood: platelets, which primarily govern blood clotting, and a subset of white blood cells.

Alpaugh explains: “At a molecular level, platelets share many characteristics with neurons so tau levels may be a really useful tool to track disease progression using the blood.”

The study compared blood samples collected from patients at HD clinics in Canada and the United Kingdom. Alpaugh and colleagues isolated the platelets and white blood cells from the patients’ samples and measured levels of tau.

Some of the changes to tau that occur in other neurodegenerative diseases include phosphorylation and fragmentation of the protein, both of which are related to disease severity.  That meant that the team was looking for fragmented and phosphorylated tau, in addition to intact tau.

They found that, as a group, patients with manifest HD had elevated levels of both intact and fragmented tau, depending on the part of the blood analysed, and that these levels increased as disease severity worsened.

They also found that specific patterns of tau phosphorylation were associated with increased disease severity and/or the later stages of the disease.

When tau levels were compared to cognition tests conducted at the time of blood collection, the researchers discovered that different forms of tau were also related to aspects of motor control, cognitive function, and completion of daily tasks.

While tau was found in both platelets and white blood cells, it proved to be most informative in platelets. The team was able to use tau levels in platelets to classify specific stages of HD, setting the stage for using tau in blood as a biomarker to track disease progression.   

“Identifying these types of biomarkers is important,” says Alpaugh. “Fundamental research like this lays the groundwork for developing dynamic treatments that target the pathways most affected by the disease.”

Read the full story in the Journal of Neurology.

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