Miller School Study Could Lead to Neuroprotective Therapy for Huntington’s Disease

A laboratory study by University of Miami Miller School of Medicine researchers could lead to a new treatment strategy for Huntington’s disease, an incurable genetic disorder. “We discovered the neuroprotective role of a cellular ‘housekeeping’ enzyme in alleviating disease progression,” said R. Grace Zhai, Ph.D., associate professor of molecular and cellular pharmacology.

Using a fruit fly (Drosophila) model, the research team found that the enzyme Nmnat (nicotinamide mononucleotide adenylyltransferase) had a beneficial impact on mutant Huntingtin (Htt) protein aggregations that interrupt the transmission of nerve signals from the brain.

“We found that Htt aggregates become increasingly adhesive with age and trap essential components in the neurons,” said Dr. Zhai. “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.”

Dr. Zhai was corresponding author of the study, “Nmnat Restores Neuronal Integrity by Neutralizing Mutant Huntingtin Aggregates-Induced Progressive Toxicity,” published online Sept. 4 in the journal Proceedings of the National Academy of Sciences (PNAS). Miller School doctoral student Yi Zhu, M.D., who conducted most of the experiments, was first author of the study and co-authors were Chong Li, Xianzun Tao, Jennifer M. Brazill, Joun Park and Zoraida Diaz-Perez. The study research was supported by the Lois Pope LIFE Foundation Fellows Program and the National Institutes of Health.

Dr. Zhai has used Drosophila as a model organism to study other types of neurological disorders, including Alzheimer’s disease and Parkinson’s disease. “Fruit fly and human brains actually have many characteristics in common,” she said. “This model has helped us understand how the basic maintenance functions for neurons decline with age, disease or genetic disorders.”

Huntington’s disease is dominantly inherited and caused by a defective Huntingtin gene. If one parent has the mutant gene, each child has a 50 percent chance of inheriting the mutant gene, although the symptoms usually do not appear until middle age. The signs of the disease include uncontrolled movements, as well as cognitive and emotional problems, followed by gradually increasing difficulties in walking, talking and swallowing.

In Huntington’s disease, the neurons’ long, threadlike axons become vulnerable to toxic accumulations of the mutant Htt protein. “We have known the buildups become larger and more numerous with age, resulting in multiple neurological problems,” Dr. 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.”

Dr. Zhai said the Miller School study shows that increasing the level of Nmnat in the neurons after the onset of neurodegenerative symptoms can significantly mitigate disease progression even in the late stages of the disease. “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,” she said.

Tags: Dr. Grace Zhai, Huntington's disease, Proceedings of the National Academy of Sciences