Increasing the levels of a natural enzyme called nicotinamide mononucleotide adenylyltransferase — or Nmnat — halts the formation of mutant huntingtin (Htt) protein aggregates that build up in nerves cells in Huntington’s disease, a fruit fly study shows.
“We discovered the neuroprotective role of a cellular ‘housekeeping’ enzyme in alleviating disease progression,” R. Grace Zhai, PhD, associate professor of molecular and cellular pharmacology at the University of Miami Miller School of Medicine and the study’s lead author, said in a press release.
The study, “Nmnat Restores Neuronal Integrity by Neutralizing Mutant Huntingtin Aggregates-Induced Progressive Toxicity,” was published in the journal PNAS.
Huntington’s disease is characterized by mutations in the HTT gene, which results in the abnormal production and accumulation of mutated forms of the huntingtin (HTT) protein inside nerve cells, ultimately causing them to die.
However, the mechanisms by which the mutated HTT triggers neuronal death remains unclear.
To learn more, researchers at the University of Miami Miller School of Medicine used a fruit fly model of Huntington’s disease with many characteristics that resemble those found in the human brain.
“Fruit fly and human brains actually have many characteristics in common,” Zhai said. “This model has helped us understand how the basic maintenance functions for neurons decline with age, disease or genetic disorders.”
The team had previously observed that an enzyme called Nmnat — officially nicotinamide mononucleotide adenylyltransferase — had neuroprotective properties. It aided in clearing toxic tau protein aggregates in a fly model of frontotemporal dementia with parkinsonism.
Now, they tested the neuroprotective properties of Nmnat in Huntington’s disease.
The researchers first observed that the Htt aggregate, or clumps, increased in size as the flies aged. This impaired the release of neurotransmitters — chemical substances that allow cells to communicate — from nerve cells.
Nmnat was localized within the Htt aggregates, and increasing the levels of Nmnat significantly reduced the size of the clumps within the neurons.
“We found that Htt aggregates become increasingly adhesive with age and trap essential components in the neurons,” Zhai said. “Nmnat helps to reduce that Htt accumulation and provides a surface coating against that stickiness, resulting in an immediate improvement in the neuron’s functioning.”
Previous studies have shown that the mutated Htt impairs the function of mitochondria, the cells’ powerhouses. The team found that the Nmnat enzyme reduced the progressive accumulation of mutant Htt aggregates by neutralizing its adhesiveness. That inhibited the clustering of mutant Htt with mitochondria and synaptic proteins, and enhanced its clearance through a natural cellular recycling process called autophagy. The synapses are the junctions between two nerve cells that allow them to communicate.
“We have known the buildups become larger and more numerous with age, resulting in multiple neurological problems,” Zhai said. “This study provided new insights into Htt’s adhesive chemical properties, and how we could make changes to improve the neuron’s functioning.”
Overall, these findings support the potential therapeutic benefits of Nmnat for Huntington’s disease.
Importantly, when the researchers engineered flies to express Nmnat only after the onset of Huntington’s disease, it significantly delayed the progression of neurodegeneration — “revealing the therapeutic potential of Nmnat-mediated neuroprotection at advanced stages of [the disease],” they said.
“The beneficial effect of Nmnat could be instant and regardless of disease stage, which would potentially be very attractive for therapeutic design,” the investigators added. “This will be clinically beneficial, as most therapeutic interventions are only effective in premanifest disease stages of HD when mild symptoms may be reversible, whereas disease progression becomes faster and relatively resistant to treatment when the symptoms have been fully developed.”
The team now will investigate the potential of therapies to potentiate Nmnat levels and activity.
“Our next step will involve screening drugs and compounds that could potentially increase Nmnat or enhance its ability to reduce the Htt aggregations that build up in Huntington’s disease,” Zhai said.
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