Life Sciences Research for Lifelong Health
Nerve cells

Michael Coleman

Michael Coleman is now Professor of Neuroscience in the Department of Clinical Neuroscience, University of Cambridge. Visit his page there for full details of his current research.

Research Summary

Michael studies basic mechanisms regulating axon survival. Age-related axon loss contributes to declining memory, senses, autonomic nervous system (bladder, gut, etc.) and motor function, leading to physical frailty. It also sets the biological context for age-related neurodegenerative disease.
 

Latest Publications

Low levels of NMNAT2 compromise axon development and survival.
Gilley J, Mayer P, Yu G, Coleman MP

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 PNS and CNS so a 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. Whilst 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.

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Human molecular genetics, , 1460-2083, , 2018

PMID: 30304512

Publisher Correction: TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.
White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM, Stephenson J, Yang S, Massenzio F, Lin Z, Andrews S, Segonds-Pichon A, Metterville J, Saksida LM, Mead R, Ribchester RR, Barhomi Y, Serre T, Coleman MP, Fallon JR, Bussey TJ, Brown RH, Sreedharan J

In the version of this article initially published, the footnote number 17 was missing from the author list for the two authors who contributed equally. Also, the authors have added a middle initial for author Justin R. Fallon and an acknowledgement to the Babraham Institute Imaging Facility and Sequencing Core Facility. The errors have been corrected in the HTML and PDF versions of the article.

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Nature neuroscience, , 1546-1726, , 2018

PMID: 29872124

Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.
Adalbert R, Milde S, Durrant C, Ando K, Stygelbout V, Yilmaz Z, Gould S, Brion JP, Coleman MP

In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPT knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPT mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young MAPT knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPT impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.

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Neurobiology of aging, 68, 1558-1497, 68-75, 2018

PMID: 29729423

Group Members

Latest Publications

Low levels of NMNAT2 compromise axon development and survival.

Gilley J, Mayer P, Yu G

Human molecular genetics
1460-2083: (2018)

PMID: 30304512

Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.

Adalbert R, Milde S, Durrant C

Neurobiology of aging
68 1558-1497:68-75 (2018)

PMID: 29729423

TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.

White MA, Kim E, Duffy A

Nature neuroscience
1546-1726: (2018)

PMID: 29556029

Neuronal Cell Death.

Fricker M, Tolkovsky AM, Borutaite V

Physiological reviews
98 1522-1210:813-880 (2018)

PMID: 29488822

Sarm1 Deletion, but Not Wld(S), Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy.

Gilley J, Ribchester RR, Coleman MP

Cell reports
21 2211-1247:10-16 (2017)

PMID: 28978465

NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency In Vivo.

Di Stefano M, Loreto A, Orsomando G

Current biology : CB
1879-0445: (2017)

PMID: 28262487

Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice.

Harwell CS, Coleman MP

Molecular neurodegeneration
11 1750-1326:44 (2016)

PMID: 27287430

Traumatic Axonal Injury: Mechanisms and Translational Opportunities.

Hill CS, Coleman MP, Menon DK

Trends in neurosciences
39 1878-108X:311-24 (2016)

PMID: 27040729

Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.

Gilley J, Ando K, Seereeram A

Neurobiology of aging
39 1558-1497:1-18 (2016)

PMID: 26923397