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

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

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

Group Members

Latest Publications

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

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