Activity and Levels of Enzyme Aco2 May Be Biomarker of Huntington’s Progression, Early Study Reports
A poorly active enzyme called aconitase 2 (Aco2), found at low levels in cells, can be a marker of the mitochondrial dysfunction linked to Huntington’s disease and its progression, an early study reports.
Huntington’s disease is caused by the accumulation of huntingtin protein aggregates. This triggers several cellular and metabolic changes, including impaired mitochondria activity, increased inflammation, and oxidative stress, all of which contribute to brain cell death and disease progression.
Because of the metabolic complexity underlying Huntington’s, it can be difficult to recognize its signs and assess its development. New and more accurate biomarkers for this reason are needed.
Analyses of the molecular profile presented by animal models of Huntington’s disease, as well as by patients, have allowed researchers to identify potential disease biomarkers. This was the case with the enzyme Aco2, which was found to be significantly reduced in leukocytes of people with Huntington’s compared to healthy individuals. (Enzymes are efficient and specific catalyst proteins that regulate biochemical reactions, and are found in all cells.)
Aco2 is critical in the conversion of citrate into isocitrate, an important step in the process of cellular energy production by mitochondria.
Because mitochondria dysfunction is an important contributor to Huntington’s, investigators at Chang-Gung University, in Taiwan, evaluated the role of Aco2 in two mouse models representing early and later stages of the disease.
Analysis of the enzyme’s levels in the brain showed that animal with early-stage disease had similar amounts of Aco2 as healthy mice. But mice with later-stage Huntington’s had notably lower levels of the enzyme, which decreased as the disease progressed.
When the investigators evaluated the enzyme’s activity they found that Aco2 was less active in the striatum region — the brain area that is most affected by neuronal death in Huntington’s disease — in both mouse models.
Aco2 activity can be limited by the presence of reactive oxygen elements. So the team treated mice with an anti-oxidant and then re-measured the enzyme’s activity in their brains. The animals showed significantly improved enzyme activity, and slower disease progression.
To confirm these findings, the team then tested lymphocytes and monocytes — both immune system cells — collected from patients’ blood and from pre-symptomatic people who were carriers of the HTT mutation, Huntington’s genetic hallmark.
The researchers found that Huntington’s patients had decreased Aco2 levels and activity. Asymptomatic carriers showed only lesser enzyme activity compared to healthy people, but enzyme levels were unchanged, a finding that was similar to what was seen in the mice.
Additional analysis revealed that the activity of the enzyme was correlated with both the patients’ functional abilities and disease duration. Lower functional and motor scores, as well as more advanced disease, were associated with lower Aco2 activity.
The team believes that these findings further demonstrate the important role of mitochondria in Huntington’s disease development. In addition, their work showed Aco2 to be a potential biomarker of Huntington’s susceptibility and development.
“The decreased Aco2 activity without changes in Aco2 protein level in PBMC [peripheral blood mononuclear cells] of PreHD [Huntington’s] carriers also implicates that inactivation of Aco2 precedes protein degradation in HD,” the researchers wrote. “The reduction is correlated significantly with disease severity … as well as disease duration.
“Therefore, Aco2 activity may serve a potential biomarker for indicating disease status and testing [the] efficacy of future therapeutic strategies. Our study also suggests Aco2 as a potential target of the HD treatment and means to enforce Aco2 activity or decrease oxidative stress will be beneficial to HD patients,” the concluded, adding that further study is needed in patients and carriers to support Aco2 as a disease biomarker.