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Researchers find enzyme plays much larger role in preventing neurodegenerative diseases

Researchers find enzyme plays much larger role in preventing neurodegenerative diseases
Deleting NMNAT2 in cortical glutamatergic neurons results in age-dependent axonal degeneration. A Body weight of cKO and their littermate control (ctrl) mice at P4/5, P16/21, P60, and P90. Mice numbers: 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. B Movie screenshots showing that a P90 cKO mouse exhibits hindlimb clasping behaviors (dashed white oval), a classic motor deficit observed in many neurodegenerative models (see Sup. Movies), but not in a ctrl mouse. C, D Bright field images showing whole brains and coronal plane brain sections (rostral to caudal from left to right) from ctrl and cKO mice. In addition to the smaller brain sizes, cKO brains have enlarged ventricles and reduced cortical regions and hippocampal areas. E Quantification of the primary somatosensory (S1) cortex thickness in ctrl and cKO mice at different ages. Mice numbers: P4/5, 6 ctrl and 7 cKO; P16/P21, 14 ctrl and 9 cKO; P90, 4 ctrl and 4 cKO. F Confocal images of immunohistochemical staining of NFM (medium-size neurofilament) showing axonal tracts through the corpus callosum (CC) in ctrl and cKO brains at P4, P21, and P90. Yellow brackets mark the thickness of the CC. G Quantification of the CC thickness, normalized to its value in ctrl mice. Mice numbers: 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; Hi, hippocampus; St, striatum; VC, ventricle. Unpaired t-test and Mann–Whitney test were applied for the statistic result, ***p < 0.001, ****p < 0.0001. Credit: Molecular Neurodegeneration (2024). DOI: 10.1186/s13024-023-00690-9

Indiana University researchers in the College of Arts and Sciences in Bloomington have identified a missing link that can help protect the brain from aging.

Hui-Chen Lu, professor and director of the Linda and Jack Gill Center for Biomolecular Science at IU, alongside graduate students Sen Yang and Zhen Xian Niou, found that nicotinamide nucleotide adenylyl transferase 2, or NMNAT2, provides energy to axons independent of the mitochondria.

It does this by propelling glycolysis, a process in which glucose is broken down to produce energy. This gives axons enough energy to carry out to the brain and other parts of the body, keeping them healthy and functional. The enzyme can play a critical role in fending off like ALS, Alzheimer's, Huntington's and Parkinson's 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 one 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 infection. Often, axon damage is the first sign of neurodegenerative disease, but their protection can delay neurodegeneration.

Axons quickly convey information throughout the entire body, a process of traveling long distances within an extremely short time scale that requires significant amounts of energy. However, the , widely known as the cellular powerhouse, are in relatively sparse density in .

NMNAT2 is a vital provider of nicotinamide adenine dinucleotide for the brain. NAD has been studied intensively for its regenerative properties and is sometimes referred to as the "fountain of youth."

"This new finding showcases the importance of neuron-intrinsic glycolysis in supporting , essential for the establishment and maintenance of neuronal circuitry," Lu said. "With this information, the next step could be designing drugs to target NMNAT2 to boost its expression or activity in pre-symptomatic stages of neurodegeneration."

Lu's laboratory has studied NMNAT2 extensively, publishing research in 2017 which found that caffeine, along with 23 other compounds, can increase the body's production of NMNAT2. In 2016, Lu published a study that found those 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 fast axonal transport, Molecular Neurodegeneration (2024). DOI: 10.1186/s13024-023-00690-9

Provided by Indiana University
Citation: Researchers find enzyme plays much larger role in preventing neurodegenerative diseases (2024, January 31) retrieved 24 April 2024 from
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