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. He remains an Affiliate Scientist at the Babraham Institute.
 

Research Summary

We study 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.
 
We identified a protein that delays degeneration of injured axons, or Wallerian degeneration, by tenfold. We investigate its mechanism and the pathway on which it acts, including signalling by pyridine nucleotides and a Toll-like receptor adapter. In line with BBSRC’s strategic priority ‘Healthy Ageing across the Lifecourse’, we study the contribution of this mechanism to age-related axon loss.

For example, we find that axonal transport of NMNAT2 is essential for axon survival but this transport declines during normal ageing. Consequently, we are testing whether depleting NMNAT accelerates age-related axon loss and whether blocking the pathway delays it.  
 
In knowledge exchange activities with Alzheimer’s Research UK, the Motor Neuron Disease Association and Takeda Cambridge Ltd, we also study axons in age-related disease. We investigate dystrophic axons in Alzheimer’s disease, modifiers of axon loss in amyotrophic lateral sclerosis and axonal transport in peripheral neuropathy.
 
In summary, our primary aim is to understand processes within axons that enable these remarkable cellular structures up to one metre long to survive for over 80 years. In parallel, we maximise the exchange of knowledge, skills and resources with research into age-related diseases. Understanding normal ageing is essential for a full understanding of age-related neurodegeneration.

Latest Publications

Sarm1 Deletion, but Not Wld(S), Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy.
Gilley J, Ribchester RR, Coleman MP

Studies with the Wld(S) mutant mouse have shown that axon and synapse pathology in several models of neurodegenerative diseases are mechanistically related to injury-induced axon degeneration (Wallerian degeneration). Crucially, an absence of SARM1 delays Wallerian degeneration as robustly as Wld(S), but their relative capacities to confer long-term protection against related, non-injury axonopathy and/or synaptopathy have not been directly compared. While Sarm1 deletion or Wld(S) can rescue perinatal lethality and widespread Wallerian-like axonopathy in young NMNAT2-deficient mice, we report that an absence of SARM1 enables these mice to survive into old age with no overt phenotype, whereas those rescued by Wld(S) invariantly develop a progressive neuromuscular defect in their hindlimbs from around 3 months of age. We therefore propose Sarm1 deletion as a more reliable tool than Wld(S) for investigating Wallerian-like mechanisms in disease models and suggest that SARM1 blockade may have greater therapeutic potential than WLD(S)-related strategies.

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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, Mori V, Zamporlini F, Hulse RP, Webster J, Donaldson LF, Gering M, Raffaelli N, Coleman MP, Gilley J, Conforti L

Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive. Injury or genetically induced depletion of NMNAT2 triggers axonal degeneration or defective axon growth. We have previously proposed that axonal NMNAT2 primarily promotes axon survival by maintaining low levels of its substrate NMN rather than generating NAD; however, this is still debated. NMN deamidase, a bacterial enzyme, shares NMN-consuming activity with NMNAT2, but not NAD-synthesizing activity, and it delays axon degeneration in primary neuronal cultures. Here we show that NMN deamidase can also delay axon degeneration in zebrafish larvae and in transgenic mice. Like overexpressed NMNATs, NMN deamidase reduces NMN accumulation in injured mouse sciatic nerves and preserves some axons for up to three weeks, even when expressed at a low level. Remarkably, NMN deamidase also rescues axonal outgrowth and perinatal lethality in a dose-dependent manner in mice lacking NMNAT2. These data further support a pro-degenerative effect of accumulating NMN in axons in vivo. The NMN deamidase mouse will be an important tool to further probe the mechanisms underlying Wallerian degeneration and its prevention.

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Current biology : CB, , 1879-0445, , 2017

PMID: 28262487

KIF1A mediates axonal transport of BACE1 and identification of independently moving cargoes in living SCG neurons.
Hung CO, Coleman MP

Neurons rely heavily on axonal transport to deliver materials from the sites of synthesis to the axon terminals over distances that can be many centimetres long. KIF1A is the neuron-specific kinesin with the fastest reported anterograde motor activity. Previous studies have shown that KIF1A transports a subset of synaptic proteins, neurofilaments and dense-core vesicles. Using two-colour live imaging, we showed that BACE1-mCherry moves together with KIF1A-GFP in both the anterograde and retrograde directions in SCG neurons. We confirmed that KIF1A is functionally required for BACE1 transport by using KIF1A siRNA and a KIF1A mutant construct (KIF1A-T312M) to impair its motor activity. We further identified several cargoes that have little or no co-migration with KIF1A-GFP and also move independently from BACE1-mCherry. Together, these findings support a primary role for KIF1A in the anterograde transport of BACE1 and suggest that axonally transported cargoes are sorted into different classes of carrier vesicles in the cell body and are transported by cargo-specific motor proteins through the axon.

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Traffic (Copenhagen, Denmark), , 1600-0854, , 2016

PMID: 27484852

Group Members

Latest Publications

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

Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

Rodríguez-Martín T, Pooler AM, Lau DH

Neurobiology of disease
85 1095-953X:1-10 (2015)

PMID: 26459111

Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses.

Mundinger TO, Cooper E, Coleman MP

American journal of physiology. Endocrinology and metabolism
309 1522-1555:E246-55 (2015)

PMID: 26037249

Absence of SARM1 rescues development and survival of NMNAT2-deficient axons.

Gilley J, Orsomando G, Nascimento-Ferreira I

Cell reports
10 2211-1247:1974-81 (2015)

PMID: 25818290

Axonal transport declines with age in two distinct phases separated by a period of relative stability.

Milde S, Adalbert R, Elaman MH

Neurobiology of aging
1558-1497: (2014)

PMID: 25443288

The Axon-Protective WLD(S) Protein Partially Rescues Mitochondrial Respiration and Glycolysis After Axonal Injury.

Godzik K, Coleman MP

Journal of molecular neuroscience : MN
1559-1166: (2014)

PMID: 25352062