BLOOMINGTON, Ind.—Biomedical researchers at Indiana University (IU) have uncovered evidence that the enzyme NMNAT2 may help protect against the effects of degenerative diseases such as Alzheimer’s, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.
The research was led by Hui-Chen Lu, the Gill Professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, a part of the IU Bloomington College of Arts and Sciences. First author Yousuf Ali, an IU research scientist, and three other members of Lu’s lab conducted the work in collaboration with researchers from the Baylor College of Medicine, Massachusetts Institute of Technology (MIT), Rush University, University of Texas and Harvard University. The results were published in PLOS Biology.
“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.”
Neurodegenerative disorders are caused by accumulations of proteins inside the brain. Conditions called proteinopathies are caused when proteins misfold and grow “sticky,” forming clumps in the brain called plaques or tangles. NMNAT2 acts as a molecular chaperone, binding to these misfolds to prevent, or even repair, the errors that cause these clumps. Over 600 million people in America alone suffer from neurodegenerative diseases, with Alzheimer’s patients being estimated at factoring in over 500,000 deaths in 2010 alone.
Lu and colleagues established a clinical study in 1997 examining the brains of over 500 elderly people whose cognitive function was tested annually. They found that brains with higher levels of NMNAT2 had a greater resistance to cognitive decline, while lower levels were more likely to develop dementia. These findings suggest that the protein helps preserve the neurons related to learning and memory.
“Maintaining neuronal health is key to preventing neurodegeneration and dementia,” Lu said.
“This is a fresh look at neurodegenerative disorders,” Ali added.
Using such a broad human database, Lu’s team was able to form, and later test, their hypothesis in mice whose brains had been damaged by Tau, a toxic protein associated with disease progression. By increasing the levels of NMNAT2 in the hippocampus, a part of the brain that correlates with learning and memory, they noted significantly lowered levels of Tau.
“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.”
This study started in Lu’s lab at Baylor College of Medicine and was continued by Ali at IU under Lu’s direction, along with Dena Bakhshizadehmahmoudi and Hunter M. Allen. Additional authors are Bellen, Asante Hatcher, David Li-Kroeger and Shulman of Baylor; Bennett and Lei Yu of Rush University; De Jager, Cristin McCabe and Jishu Xu of MIT; and Nicole Bjorklund and Giulio Taglialatela of University of Texas Medical Branch-Galveston. Jager is also affiliated with Harvard Medical School. Lu joined the Gill Center at IU Bloomington in 2015.
This research was supported in part by the National Institutes of Health and the Robert A. and Renee E. Belfer Family Foundation.