Researchers have identified an enzyme that may help protect against the debilitating effects of certain degenerative brain diseases such as Alzheimer’s, an advance which could assist in the development of new drugs.
This 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 ageing, said Hui-Chen Lu from Indiana University (IU) in the US.
Many neuro-degenerative disorders are caused by accumulation of proteins in the brain. These conditions, called proteinopathies, occur when proteins ‘misfold’, causing them to grow ‘sticky’ and clump up in the brain in a form often referred to as ‘plaques’ or ‘tangles’ researchers said. As a molecular chaperone, NMNAT2 binds to misfolded proteins to prevent or repair the errors that cause these clumps, they said. Common proteinopathies are Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease, researchers said.
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By examining NMNAT2 levels in brains donated by more than 500 elderly people whose cognitive function was tested annually before death – starting with the year of their enrollment in a clinical study established in 1997 – researchers found higher levels of NMNAT2 in people who had greater resistance to cognitive decline. People with lower NMNAT2 were more likely to suffer from dementia, suggesting that the protein helps preserve neurons related to learning and memory.
Researchers tested this hypothesis in mice whose brains were damaged by high levels of Tau, a toxic protein that correlates with disease progression. They found that increasing the level of NMNAT2 in the hippocampus, a brain region important for learning and memory, significantly lowered levels of Tau. Maintaining neuronal health is key to preventing neurodegeneration and dementia” said Lu. This is a fresh look at neurodegenerative disorders, added Yousuf Ali from IU. The power of statistics using large and comprehensive human data sets allowed researchers to form a testable hypothesis and then examine it in pre-clinical animal models to demonstrate causal relationships.
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, said Lu.
The findings were published in journal PLOS Biology.