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

NAD cleavage activity by animal and plant TIR domains in cell death pathways.
Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX, Casey LW, Gu W, Ericsson DJ, Foley G, Hughes RO, Bosanac T, von Itzstein M, Rathjen JP, Nanson JD, Boden M, Dry IB, Williams SJ, Staskawicz BJ, Coleman MP, Ve T, Dodds PN, Kobe B

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

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Science (New York, N.Y.), 365, 1095-9203, 793-799, 2019

PMID: 31439792

Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence.
Lukacs M, Gilley J, Zhu Y, Orsomando G, Angeletti C, Liu J, Yang X, Park J, Hopkin RJ, Coleman MP, Zhai RG, Stottmann RW

The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and hydrops fetalis. Clinical exome sequencing identified compound heterozygous NMNAT2 variant alleles in both cases. Both protein variants are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein stability and/or defects in NAD synthesis and chaperone functions. Thus, both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder. SIGNIFICANCE: Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) both synthesizes the electron carrier Nicotinamide Adenine Dinucleotide (NAD) and acts a protein chaperone. NMNAT2 has emerged as a major neuron survival factor. Overexpression of NMNAT2 protects neurons from Wallerian degeneration after injury and declining levels of NMNAT2 have been implicated in neurodegeneration. While the role of NMNAT2 in neurodegeneration has been extensively studied, the role of NMNAT2 in human development remains unclear. In this work, we present the first human variants in NMNAT2 identified in two fetuses with severe skeletal muscle hypoplasia and fetal akinesia. Functional studies in vitro showed that the mutations impair both NMNAT2 NAD synthase and chaperone functions. This work identifies the critical role of NMNAT2 in human development.

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Experimental neurology, 320, 1090-2430, 112961, 2019

PMID: 31136762

Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia.
Huppke P, Wegener E, Gilley J, Angeletti C, Kurth I, Drenth JPH, Stadelmann C, Barrantes-Freer A, Brück W, Thiele H, Nürnberg P, Gärtner J, Orsomando G, Coleman MP

We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia. No additional homozygotes for this rare allele, which leads to amino acid substitution T94M, were present among the unaffected relatives tested or in the 60,000 exomes of the ExAC database. For axons to survive, axonal NMNAT2 activity has to be maintained above a threshold level but the T94M mutation confers a partial loss of function both in the ability of NMNAT2 to support axon survival and in its enzymatic properties. Electrophysiological tests and histological analysis of sural nerve biopsies in the patients were consistent with loss of distal sensory and motor axons. Thus, it is likely that NMNAT2 mutation causes this pain and axon loss phenotype making this the first disorder associated with mutation of a key regulator of Wallerian-like axon degeneration in humans. This supports indications from numerous animal studies that the Wallerian degeneration pathway is important in human disease and raises important questions about which other human phenotypes could be linked to this gene.

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Experimental neurology, 320, 1090-2430, 112958, 2019

PMID: 31132363

 

Group Members

Latest Publications

NAD cleavage activity by animal and plant TIR domains in cell death pathways.

Horsefield S, Burdett H, Zhang X

Science (New York, N.Y.)
365 1095-9203:793-799 (2019)

PMID: 31439792

Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia.

Huppke P, Wegener E, Gilley J

Experimental neurology
320 1090-2430:112958 (2019)

PMID: 31132363

A closer look at neuron interaction with track-etched microporous membranes.

George JH, Nagel D, Waller S

Scientific reports
8 2045-2322:15552 (2018)

PMID: 30341335

P7C3-A20 neuroprotection is independent of Wallerian degeneration in primary neuronal culture.

Hill CS, Menon DK, Coleman MP

Neuroreport
1473-558X: (2018)

PMID: 30334859

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