A new study led by biomedical scientists at Indiana University has revealed evidence that the NMNAT2 enzyme may be protective against the debilitating effects of certain degenerative disorders, including Alzheimer’s Disease.
The study, “NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies,” was published in the journal PLOS Biology.
According to a news release, the study found that NMNAT2, or nicotinamide mononucleotide adenylyl transferase 2, is a key neuronal maintenance factor.
“It exerts both an enzyme function to protect neurons from stress caused by over-excitation, and a ‘chaperone’ function, shown for the first time in this study, to combat the misfolded proteins encountered by the brain during aging.” said Hui-Chen Lu, a professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, at IU Bloomington College of Arts and Sciences.
Many neurodegenerative diseases result from the build-up of certain proteins in the brain. These disorders, called proteinopathies, occur when proteins “misfold,” causing them build-up in the brain in the form of plaques or “tangles.” NMNAT2 binds to misfolded proteins and repair or prevent the faults that cause the build-up.
The most common proteinopathies are Parkinson’s, Huntington’s, and Alzheimer’s diseases, and amyotrophic lateral sclerosis.
In the new study, Lu and colleagues that included first author Yousuf Ali, an IU research scientist, examined NMNAT2 levels in brains donated by more than 500 elderly people who had cognitive function tested yearly before death. The researchers found higher levels of NMNAT2 in the patients who were more resistant to cognitive deterioration, and that those people who had lower levels of NMNAT2 were more likely to suffer from dementia.
According to researchers, the results suggest that the NMNAT2 protein can protect the neurons associated with memory and learning.
The team of scientists then tested the theory in mice with brains damaged by high Tau levels, a toxic protein that is associated with the progression of neurodegenerative diseases. They discovered that by increasing the levels of the NMNAT2 protein in the hippocampus (a brain area associate with memory and learning), they decreased the levels of the Tau protein.
“Maintaining neuronal health is key to preventing neurodegeneration and dementia,” Lu said.
“This is a fresh look at neurodegenerative disorders,” Ali said.
The statistical power of using large and broad human data sets allowed the research team to create a testable theory and then assess it in preclinical animal models to establish causal relationships.
“Such studies are only possible through multidisciplinary team efforts, and we are extremely grateful for our wonderful collaborators and funding support,” Lu said. “A detailed knowledge of how NMNAT2 maintains neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function but also for providing necessary insights to assist in the development of new drugs.”
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