Deletion of NMNAT2 in cortical glutamatergic neurons results in age-dependent axonal degeneration. A Body weight of cKO and their control mice (ctrl) at P4/5, P16/21, P60 and P90. Number of mice: P4/5, 13 ctrl and 9 cKO; P16/P21 43 ctrl and 46 cKO; P60, 7 ctrl and 8 cKO; P90, 6 ctrl and 10 cKO. Screenshots from Movie B showing that a P90 cKO mouse exhibits hindlimb clenching behaviors (dashed white oval), a classic motor deficit observed in many neurodegenerative models (see Sup. Movies), but not in a mouse ctrl. C, D Bright-field images showing whole brains and brain sections from the coronal plane (rostral to caudal from left to right) of ctrl and cKO mice. In addition to reduced brain size, cKO brains have enlarged ventricles and reduced cortical and hippocampal regions. E Quantification of the thickness of the primary somatosensory cortex (S1) in ctrl and cKO mice at different ages. Number of mice: P4/5, 6 ctrl and 7 cKO; P16/P21, 14 ctrl and 9 cKO; P90, 4 ctrl and 4 cKO. F Confocal images of NFM (medium-sized neurofilament) immunohistochemical staining showing axonal pathways through the corpus callosum (CC) in ctrl and cKO brains at P4, P21, and P90. The yellow parentheses mark the thickness of the CC. G Quantification of CC thickness, normalized to its value in ctrl mice. Number of mice: P4/5, 5 ctrl and 5 cKO; P16/P21, 9 ctrl and 7 cKO; P90, 3 ctrl and 3 cKO. Abbreviations: Ac, anterior commissure; IC, internal capsule; CC, corpus callosum; CX, cortex; Hello, seahorse; St, striatum; CV, ventricle. Unpaired t test and Mann–Whitney test were applied for statistical result, ***p < 0.001, ****p < 0.0001. Credit: Molecular neurodegeneration (2024). DOI: 10.1186/s13024-023-00690-9
Researchers at Indiana University Bloomington’s College of Arts and Sciences have identified a missing link that may help protect the brain from aging.
Hui-Chen Lu, professor and director of the Linda and Jack Gill Center for Biomolecular Sciences at IU, alongside graduate students Sen Yang and Zhen Xian Niou, discovered that nicotinamide nucleotide adenylyl transferase 2, or NMNAT2, provides energy to axons independently of mitochondria. .
It does this by powering glycolysis, a process in which glucose is broken down to produce energy. This gives the axons enough energy to transmit nerve impulses to the brain and other parts of the body, keeping them healthy and functional. The enzyme may play a vital role in fighting neurodegenerative diseases like ALS, Alzheimer’s disease, Huntington’s disease and Parkinson’s disease as people age.
The study appears in Molecular neurodegeneration.
Axons are long, thin fibers that connect nerve cells and allow them to communicate with each other. Axons are typically a micrometer in diameter, several times thinner than a human hair, making them vulnerable and easily damaged by inflammation, trauma, reduced blood flow to the brain and infections. Often, axonal damage is the first sign of a neurodegenerative disease, but protecting it can delay neurodegeneration.
Axons transmit information rapidly throughout the body, a process for traveling long distances in an extremely short period of time that requires significant amounts of energy. However, mitochondria, widely known as the cellular powerhouse, have a relatively sparse density in axons.
NMNAT2 is an essential supplier of nicotinamide adenine dinucleotide to the brain. NAD has been studied extensively for its regenerative properties and is sometimes referred to as the “fountain of youth.”
“This new finding highlights the importance of intrinsic neuronal glycolysis in supporting axonal transport, which is essential for the establishment and maintenance of neuronal circuits,” said Lu. “With this information, the next step could be to design drugs targeting NMNAT2 to stimulate its expression or activity in pre-symptomatic stages of neurodegeneration.”
Lu’s lab has studied NMNAT2 extensively and published research in 2017 that found that caffeine, along with 23 other compounds, can increase the body’s production of NMNAT2. In 2016, Lu published a study that found people with higher levels of NMNAT2 had greater resistance to cognitive decline as they aged.
More information:
Sen Yang et al, NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel rapid axonal transport, Molecular neurodegeneration (2024). DOI: 10.1186/s13024-023-00690-9
Provided by Indiana University
Quote: Researchers discover enzyme plays much more important role in preventing neurodegenerative diseases (January 31, 2024) retrieved January 31, 2024 from
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