Low levels of NMNAT2 compromise axon development and survival.
View / Open Files
Authors
Gilley, Jonathan
Mayer, Paul R
Yu, Gang
Coleman, Michael P
Publication Date
2019-02-01Journal Title
Hum Mol Genet
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Volume
28
Issue
3
Pages
448-458
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
Gilley, J., Mayer, P. R., Yu, G., & Coleman, M. P. (2019). Low levels of NMNAT2 compromise axon development and survival.. Hum Mol Genet, 28 (3), 448-458. https://doi.org/10.1093/hmg/ddy356
Abstract
Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an endogenous axon maintenance factor that preserves axon health by blocking Wallerian-like axon degeneration. Mice lacking NMNAT2 die at birth with severe axon defects in both the peripheral nervous system and central nervous system so the complete absence of NMNAT2 in humans is likely to be similarly harmful but probably rare. However, there is evidence of widespread natural variation in human NMNAT2 mRNA expression so it is important to establish whether reduced levels of NMNAT2 have consequences that impact health. While mice that express reduced levels of NMNAT2, either those heterozygous for a silenced Nmnat2 allele or compound heterozygous for one silenced and one partially silenced Nmnat2 allele, remain overtly normal into old age, we now report that Nmnat2 compound heterozygote mice present with early and age-dependent peripheral nerve axon defects. Compound heterozygote mice already have reduced numbers of myelinated sensory axons at 1.5 months and lose more axons, likely motor axons, between 18 and 24 months and, crucially, these changes correlate with early temperature insensitivity and a later-onset decline in motor performance. Slower neurite outgrowth and increased sensitivity to axonal stress are also evident in primary cultures of Nmnat2 compound heterozygote superior cervical ganglion neurons. These data reveal that reducing NMNAT2 levels below a particular threshold compromises the development of peripheral axons and increases their vulnerability to stresses. We discuss the implications for human neurological phenotypes where axons are longer and have to be maintained over a much longer lifespan.
Keywords
Age Factors, Animals, Axons, Female, Male, Mice, Nerve Degeneration, Neurogenesis, Neurons, Nicotinamide-Nucleotide Adenylyltransferase, Primary Cell Culture
Sponsorship
Medical Research Council (MR/N004582/1)
Identifiers
External DOI: https://doi.org/10.1093/hmg/ddy356
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287978
Rights
Licence:
http://www.rioxx.net/licenses/all-rights-reserved
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk