Miller School Scientist Identifies Neuroprotective ‘Switch’ in Fruit Flies

A University of Miami Miller School of Medicine scientist has identified a neuroprotective “switch” in a protein found in both fruit flies and humans. That finding, by a research team led by R. Grace Zhai, Ph.D., associate professor of molecular and cellular pharmacology, which was published recently in the journal Nature Communications, could potentially lead to new clinical strategies for treating patients with Alzheimer’s disease and other neurodegenerative conditions.

“Normally, this protein — nicotinamide mononucleotide adenylyltransferase (Nmnat) — performs basic cellular housekeeping functions,” said Zhai. “But when the body’s nervous system is placed in a stressful condition, it releases substances to protect neuron cells. Eventually, we may be able to trigger that neuroprotective function in a clinical setting and possibly stabilize the disease process.”

Zhai was the senior author of the study, “Alternative Splicing of Drosophila Nmnat Functions as a Switch to Enhance Neuroprotection Under Stress.” The study’s first and co-authors — Kai Ruan, Yi Zhu, Chong Li, and Jennifer M. Brazil — are Miller School graduate students who work in Zhai’s laboratory.

“Dr. Zhai’s study is an important contribution to the field of neurodegenerative diseases and may lead to new therapeutic strategies for conferring neuroprotection,” said Charles W. Luetje, Ph.D., professor and Chair of the Department of Molecular and Cellular Pharmacology.

For the past decade, Zhai’s research has focused on understanding the mechanisms that lead to neurodegenerative diseases.

“Unlike most of the body’s cells, which are constantly dying and being replaced, neurons in the brain, spinal cord and nervous system are large complex cells designed to last the entire human life span,” she said. “When healthy, neurons can maintain their functionality for 100 years or longer, due to neuroprotective processes.”

Using Drosophila (fruit flies) in her laboratory models, Zhai has studied the key pathways for maintaining neuron health, including a protective function in the fruit flies’ visual system, which protects the retina even under stressful conditions that would normally cause degeneration.

Zhai’s latest study found that in fruit flies the protein Nmnat can produce four different protein isoforms with very divergent neuroprotective capacities. “While the four isoforms have similar chemistry, the shortest version is highly neuroprotective, but the longer isoform is not,” she said. “Our results indicate that neurons respond to stress by driving a ‘splicing switch’ to produce the neuroprotective variant and therefore achieve self-protection.”

Noting that Nmnat has existed for billions of years and is found in all animals with a nervous system, Zhai said further studies will be needed to identify the genetic regulator that “switches” production from one isoform to another.

“Once we identify those regulators, we may be able to target them by introducing small molecules and compounds,” she said. “That could be a major advance in therapeutic strategies for patients with neurodegenerative diseases.”

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