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

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 J, Bussey TJ, Brown RH, Sreedharan J

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a new approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

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Nature neuroscience, , 1546-1726, , 2018

PMID: 29556029

Neuronal Cell Death.
Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC

Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer's disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.

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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

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

Group Members

Latest Publications

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

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