High glucose levels might compensate for the toxic effects of an accumulation of TDP-43 — a widely expressed nuclear protein that binds both DNA and RNA — and protect neurons in amyotrophic lateral sclerosis (ALS), a study in a fly model of the disease suggests.
The study, “Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS,” was published in the journal eLIFE.
The brain is the organ that most relies on glucose, or sugar, to function, taking up one-fifth of the total glucose available in the body. People with ALS present weight loss and a metabolic dysregulation called hypermetabolism – defined as a significant increase in energy uptake – from the early stages of the disease. However, it is unclear how these metabolic changes relate to the loss of motor neurons, the primary symptom of ALS.
A Phase 2 clinical trial (NCT00983983) showed that a diet rich in carbohydrates was well-tolerated by ALS patients, and that it reduced adverse events related to the disease.
“Taken together, these findings suggest that although defective glucose metabolism is still poorly understood in ALS, there lies a great opportunity to better understand its relationship to disease and explore its potential as a therapeutic avenue,” the researchers said.
An essential process related to neurodegeneration in ALS is TDP-43 proteinopathy, the formation of toxic aggregates, or clusters, of the protein TDP-43. A team of researchers from the University of Arizona, and the University of Montpellier, in France, decided to study the relationship between TDP-43 accumulation and glucose metabolism.
To do so, they used a model of a fruit fly (Drosophila melanogaster) that overproduces human TDP-43 and shows some aspects of ALS, such as defects in mobility and reduced lifespan.
The researchers found that the motor neurons of ALS flies were eating up more glucose than those of healthy flies. This also occurred in the spinal cords of people with ALS in patient-derived neurons cultured in the lab.
Feeding the ALS flies a diet rich in glucose — over five times the normal levels — improved their mobility and lifespan. Researchers then made more glucose available to the neurons of ALS flies, by increasing the number of glucose transporters on these cells. This had similar effects to the high-glucose diet. It also increased the number of connections between the neurons, and made them less likely to die, which suggests that increasing the levels of glucose acts as a neuroprotective mechanism that compensates for the toxic effects of TDP-43 accumulation.
The researchers found that excess glucose was only beneficial to ALS flies. In fact, it led to metabolic problems in the control flies. Additionally, the effects were only visible in cells from the nervous system, the investigators said. Increasing the glucose levels in muscle cells did not affect ALS flies, the study showed.
“These results suggest that while a high sugar diet is detrimental to control flies, it improves key hallmarks of motor neuron disease including locomotor dysfunction and reduced survival in ALS flies,” the researchers said.
They concluded that “increased glucose availability protects motor neurons and improves overall outcome in models of TDP-43 proteinopathy.” The investigators suggested that future studies should focus on the link between different aspects of glucose metabolism, such as oxidative stress and ALS.