Moonlighting enzyme protects against degenerative brain disease

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Several major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS or "motor neuron disease"), are caused by accumulation of protein clumps in the brain. More than 6 million Americans suffer from these diseases, with Alzheimer's disease alone recently estimated to have been a factor in the death of over 500,000 people in the US in 2010. A new study now reveals that a well-known enzyme in the brain has a second job protecting our neurons from this threat.

This study, led by Yousuf Ali, Hui-Chen Lu, and colleagues at Indiana University and publishing in PLOS Biology this week, has found evidence that an enzyme known as NMNAT2 may help protect against the debilitating effects of certain degenerative brain diseases, including Alzheimer's. These conditions, called proteinopathies, occur when proteins do not fold into their normal and functional 3D structure but "mis-fold", causing them to grow "sticky" and clump up in the brain in a form often referred to as "plaques."

NMNAT2, or nicotinamide mononucleotide adenylyl transferase 2, was already well-known to scientists as an enzyme that makes nicotine adenine dinucleotide (NAD), which helps to protect our brains against a completely different type of stress – oxidative stress caused by excessive neuronal activity or "excitotoxicity." However, Lu and colleagues now reveal that NMNAT2 moonlights as a so-called "molecular chaperone," binding to misfolded proteins, helping them to re-fold properly, and preventing them from clumping.

"This study found that NMNAT2 is a key neuronal maintenance factor," Lu said. "It exerts both an enzyme function to protect neurons from over-excitation and a 'chaperone' function to combat the misfolded proteins brains encounter during aging."

Lu and colleagues examined 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 trial established in 1997. They 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.

"This is a fresh look at neurodegenerative disorders," Ali added.

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.

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In your coverage please use this URL to provide access to the freely available article in PLOS Biology: http://dx.plos.org/10.1371/journal.pbio.1002472

Citation: Ali YO, Allen HM, Yu L, Li-Kroeger D, Bakhshizadehmahmoudi D, Hatcher A, et al. (2016) NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. PLoS Biol 14(6): e1002472. doi:10.1371/journal.pbio.1002472

Funding: This work was supported by the NIH R01NS048884/NS086794 (HCL), R01AG042890 (GT), T32NS043124 (DLK), the Belfer Neurodegeneration Consortium by Belfer Family Foundation (HCL, HJB, JMS), Target ALS (HJB), the Alzheimer's Association (JMS), the American Federation for Aging Research (JMS), Burroughs Welcome Fund (JMS). HJB is a HHMI investigator. The Religious Orders Study and Rush Memory and Aging Projects are supported by NIH (R01AG30146, P30AG10161, R01AG17917, R01AG15819, K08AG034290, R01AG11101, P30AG19610, R01AG023193, R01NS059873, P50AG16574, U01AG016976, U24NS051872, P50AG23173, K01AG024079) and by the Illinois Department of Public Health. BCM-IDDRC confocal core is supported by NICHD-5P30HD024064. URLs for the funders:http://www.nih.gov/, http://www.insidephilanthropy.com/grants-for-diseases/robert-a-and-renee-e-belfer-family-foundation-grants-for-dis.html, http://www.targetals.org/, http://www.alz.org/, http://www.dph.illinois.gov/, http://www.afar.org/, http://www.bwfund.org/, http://www.hhmi.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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