An enzyme known as NMNAT2 may help protect against the debilitating effects of certain degenerative brain diseases, including Alzheimer’s, research led by biomedical researchers at Indiana University has found.
Many neurodegenerative 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.”
As a molecular chaperone, NMNAT2 binds to misfolded proteins to prevent or repair the errors that cause these clumps.
The research was led by Hui-Chen Lu, professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences.
“This study found that NMNAT2, or nicotinamide mononucleotide adenylyl transferase 2, is a key neuronal maintenance factor,” Lu said. “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."
Millions Affected By Degenerative Brain Diseases
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. More than 6 million Americans suffer from degenerative brain diseases, with Alzheimer’s disease alone recently estimated to have been a factor in the death of over 500,000 people in the U.S. in 2010.
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.
Lu and colleagues 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.
Lu’s team 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,” Lu said.
NMNAT2 In Neuroprotection
The power of statistics using large and comprehensive human data sets allowed the team to form a testable hypothesis and then examine it in preclinical animal models to demonstrate causal relationships.
“Such studies are only possible through multidisciplinary team efforts, and we are extremely grateful for our wonderful collaborators and funding support,"
said Lu, who credits the contributions of colleagues including Hugo Bellen and Joshua Shulman at Baylor, David Bennett at Rush and Philip L. De Jager at MIT.
“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,” Lu said.
Yousuf O. Ali, Hunter M. Allen, Lei Yu, David Li-Kroeger, Dena Bakhshizadehmahmoudi, Asante Hatcher, Cristin McCabe, Jishu Xu, Nicole Bjorklund, Giulio Taglialatela, David A. Bennett, Philip L. De Jager, Joshua M. Shulman, Hugo J. Bellen, Hui-Chen Lu NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies PLOS Biology, 2016; 14 (6): e1002472 DOI: 10.1371/journal.pbio.1002472
Image: GerryShaw - CC BY-SA 4.0. Neurons in tissue culture stained with antibody to MAP2 protein in green and MAP tau in red.