Variability in human axon survival
Lead Research Organisation:
University of Cambridge
Department Name: Clinical Neurosciences
Abstract
Axons are the long 'wires' that link one nerve cell to another. They are one of the first structures to be lost in almost all degenerative disorders of our brains, spinal cords and nerves. The consequences include pain, disability, loss of memory, hearing and sight in disorders such as Alzheimer's disease, motor neuron disease and multiple sclerosis. Peripheral neuropathies, disorders affecting the network of nerves outside the central nervous system, often resulting from diabetes or the side effects of cancer chemotherapy, are one example of an axonal disorder. Glaucoma, resulting from disruption of the optic nerve by pressure in the eye, is another.
There are two main ways to study axon degeneration. One is in animal or cell culture models. These model systems bring major advantages for research, for example the underlying molecular mechanism can be studied in ways that would not be possible in humans, and drugs can be tested without risk to people. However, these models often do not fully represent the corresponding human disease. They are valid because we share much of our DNA sequence and most types of cells with other mammals, but there are always some limitations.
The second, highly complementary approach is human genetics. Methods for sequencing and analysing human DNA have improved dramatically since the human genome was first sequenced and this is revolutionising our understanding of which genes may cause or contribute to common and rare disorders. However, ultimately these results are correlation rather than proof. Experimental model systems, such as those described above, are needed to extend this research.
By studying axon degeneration in mouse, cell culture and fly models, we have made substantial progress in understanding an important axon degeneration mechanism. Animal models of disease have helped us understand its potential role in human disease and in normal ageing, the single biggest risk factor for many neurodegenerative disorders. Developments in human genetics have independently suggested that the proteins regulating axon degeneration in these model systems play a role in human disease, and generated far more data on how these proteins differ within the human population. The essential next steps are to understand how variations in these proteins within the human population can affect normal protein function, so we will make similar changes in animals or cell culture models to test whether features of the corresponding human diseases emerge. Based on our knowledge of the pathway in mice we are also able to test whether blocking this pathway in various ways can prevent disease.
This work takes important steps towards translating years of progress in axon degeneration in model systems into real understanding of how the pathway malfunctions in human disease and hence towards therapies that can prevent or treat disease.
There are two main ways to study axon degeneration. One is in animal or cell culture models. These model systems bring major advantages for research, for example the underlying molecular mechanism can be studied in ways that would not be possible in humans, and drugs can be tested without risk to people. However, these models often do not fully represent the corresponding human disease. They are valid because we share much of our DNA sequence and most types of cells with other mammals, but there are always some limitations.
The second, highly complementary approach is human genetics. Methods for sequencing and analysing human DNA have improved dramatically since the human genome was first sequenced and this is revolutionising our understanding of which genes may cause or contribute to common and rare disorders. However, ultimately these results are correlation rather than proof. Experimental model systems, such as those described above, are needed to extend this research.
By studying axon degeneration in mouse, cell culture and fly models, we have made substantial progress in understanding an important axon degeneration mechanism. Animal models of disease have helped us understand its potential role in human disease and in normal ageing, the single biggest risk factor for many neurodegenerative disorders. Developments in human genetics have independently suggested that the proteins regulating axon degeneration in these model systems play a role in human disease, and generated far more data on how these proteins differ within the human population. The essential next steps are to understand how variations in these proteins within the human population can affect normal protein function, so we will make similar changes in animals or cell culture models to test whether features of the corresponding human diseases emerge. Based on our knowledge of the pathway in mice we are also able to test whether blocking this pathway in various ways can prevent disease.
This work takes important steps towards translating years of progress in axon degeneration in model systems into real understanding of how the pathway malfunctions in human disease and hence towards therapies that can prevent or treat disease.
Technical Summary
We study the pathway of axon degeneration after injury: Wallerian degeneration. Data from animal models suggest related mechanisms influence axon survival in some diseases and in ageing, including multiple sclerosis (MS), peripheral neuropathies (PN), glaucoma and some motor neuron diseases. Early axon loss is also prominent in Alzheimer's disease, Parkinson's disease and ALS. There are no disease-modifying therapies. Here, we address the role of this pathway in human axon survival.
Mutations of five genes are now known to robustly delay Wallerian degeneration in mice and other model organisms but whether a similar phenotype exists in humans has remained an intriguing but unanswered question. Recent GWAS and exome linkage between Wallerian pathway genes and ALS and a painful neuropathy, and animal studies, suggest that such a phenotype could function as a disease modifier. SNP databases indicate polymorphisms likely to delay Wallerian degeneration and others likely to confer an opposite phenotype of axon vulnerability. Our mouse and preliminary human studies support this notion.
We will test which human variants alter axon survival by testing their function in mouse neurons that lack the homologous mouse gene. Using established assays, we will ask whether human variants in a pro-survival protein, NMNAT2, support axon survival and if so how strongly, and whether variants in human SARM1, a pro-degenerative protein, restore rapid Wallerian degeneration when mouse SARM1 is missing. We will then estimate the prevalence of these phenotypes. We will test whether NMNAT2 deficiency is a risk factor for neuropathic pain, and having shown that SARM1 deletion completely rescues nerve growth and early lethality in NMNAT2 null mice, we will test whether it also rescues a premature age-related decline that we find in mice expressing low levels of NMNAT2. These data will complement ongoing GWAS and exome studies to understand the roles of this pathway in human disease.
Mutations of five genes are now known to robustly delay Wallerian degeneration in mice and other model organisms but whether a similar phenotype exists in humans has remained an intriguing but unanswered question. Recent GWAS and exome linkage between Wallerian pathway genes and ALS and a painful neuropathy, and animal studies, suggest that such a phenotype could function as a disease modifier. SNP databases indicate polymorphisms likely to delay Wallerian degeneration and others likely to confer an opposite phenotype of axon vulnerability. Our mouse and preliminary human studies support this notion.
We will test which human variants alter axon survival by testing their function in mouse neurons that lack the homologous mouse gene. Using established assays, we will ask whether human variants in a pro-survival protein, NMNAT2, support axon survival and if so how strongly, and whether variants in human SARM1, a pro-degenerative protein, restore rapid Wallerian degeneration when mouse SARM1 is missing. We will then estimate the prevalence of these phenotypes. We will test whether NMNAT2 deficiency is a risk factor for neuropathic pain, and having shown that SARM1 deletion completely rescues nerve growth and early lethality in NMNAT2 null mice, we will test whether it also rescues a premature age-related decline that we find in mice expressing low levels of NMNAT2. These data will complement ongoing GWAS and exome studies to understand the roles of this pathway in human disease.
Planned Impact
The potential non-academic beneficiaries of this project are:
(1) Pharma/biotech companies targeting neurodegenerative disorders where axon degeneration plays an important role. In particular, the move towards personalized medicine will benefit from the type of functional data we will generate. Through our Workshop organization we will also help to stimulate similar work elsewhere resulting in indirect benefit to similar companies. Axon degeneration is a significant event in most neurodegenerative diseases, including some which are highly prevalent and therefore represent major market opportunities for the commercial sector: Alzheimer's disease (lifetime risk 15%), stroke (15%), diabetic neuropathy (7%), glaucoma (2%) and Parkinson's disease (1.5%). There are no disease-modifying treatments. As explained in 'pathways to impact' we will actively engage the commercial sector to ensure this potential is realized, for example through our ongoing CASE studentship with Takeda (Cambridge).
(2) Patients with neurodegenerative disorders and their families. Understanding the genetic basis of disease is crucial. Substantial progress is being made in GWAS and exome studies but functional characterization such as we will carry out (and further stimulate through our Workshop) is vital for knowing which genes are actually causing or contributing to disease and therefore represent the right drug targets. As an increasing component of human disease is recognized to reflect genetic makeup, offering relatives the option to know whether they too are at risk will become more important. While this has important ethical considerations too, moving forward on the technological ability to do this in this work will be an important step.
(3) Lay public interested in nervous system function. In our public engagement activities we find a strong interest in the nervous system among the lay public. While there is only a limited amount that individuals can do about the health of their nervous system, understanding what goes wrong can at least help some patients to come to terms with it, and motivates some healthy individuals to ensure they avoid a lifestyle that places strains on axon survival (e.g., excessive alcohol consumption, obesity, drug abuse).
(1) Pharma/biotech companies targeting neurodegenerative disorders where axon degeneration plays an important role. In particular, the move towards personalized medicine will benefit from the type of functional data we will generate. Through our Workshop organization we will also help to stimulate similar work elsewhere resulting in indirect benefit to similar companies. Axon degeneration is a significant event in most neurodegenerative diseases, including some which are highly prevalent and therefore represent major market opportunities for the commercial sector: Alzheimer's disease (lifetime risk 15%), stroke (15%), diabetic neuropathy (7%), glaucoma (2%) and Parkinson's disease (1.5%). There are no disease-modifying treatments. As explained in 'pathways to impact' we will actively engage the commercial sector to ensure this potential is realized, for example through our ongoing CASE studentship with Takeda (Cambridge).
(2) Patients with neurodegenerative disorders and their families. Understanding the genetic basis of disease is crucial. Substantial progress is being made in GWAS and exome studies but functional characterization such as we will carry out (and further stimulate through our Workshop) is vital for knowing which genes are actually causing or contributing to disease and therefore represent the right drug targets. As an increasing component of human disease is recognized to reflect genetic makeup, offering relatives the option to know whether they too are at risk will become more important. While this has important ethical considerations too, moving forward on the technological ability to do this in this work will be an important step.
(3) Lay public interested in nervous system function. In our public engagement activities we find a strong interest in the nervous system among the lay public. While there is only a limited amount that individuals can do about the health of their nervous system, understanding what goes wrong can at least help some patients to come to terms with it, and motivates some healthy individuals to ensure they avoid a lifestyle that places strains on axon survival (e.g., excessive alcohol consumption, obesity, drug abuse).
People |
ORCID iD |
Michael Philip Coleman (Principal Investigator) |
Publications
Adalbert R
(2020)
Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.
in ACS chemical neuroscience
Clark DE
(2016)
Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.
in Bioorganic & medicinal chemistry letters
Gilley J
(2017)
Sarm1 Deletion, but Not Wld S , Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy
in Cell Reports
Gould SA
(2021)
Sarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration.
in Cell reports
Di Stefano M
(2017)
NMN Deamidase Delays Wallerian Degeneration and Rescues Axonal Defects Caused by NMNAT2 Deficiency In Vivo.
in Current biology : CB
Huppke P
(2019)
Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia.
in Experimental neurology
Lukacs M
(2019)
Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence.
in Experimental neurology
Gilley J
(2019)
Low levels of NMNAT2 compromise axon development and survival.
in Human molecular genetics
Loreto A
(2020)
Axon Degeneration Assays in Superior Cervical Ganglion Explant Cultures.
in Methods in molecular biology (Clifton, N.J.)
Gilley J
(2020)
Microinjection of Superior Cervical Ganglion Neurons for Studying Axon Degeneration.
in Methods in molecular biology (Clifton, N.J.)
Coleman MP
(2020)
Programmed axon degeneration: from mouse to mechanism to medicine.
in Nature reviews. Neuroscience
Gilley J
(2016)
Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.
in Neurobiology of aging
Rodríguez-Martín T
(2016)
Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.
in Neurobiology of disease
Loreto A
(2020)
Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration.
in Neurobiology of disease
Fricker M
(2018)
Neuronal Cell Death.
in Physiological reviews
Horsefield S
(2019)
NAD+ cleavage activity by animal and plant TIR domains in cell death pathways.
in Science (New York, N.Y.)
Coleman M
(2020)
Programmed axon degeneration: from mouse to mechanism to medicine.
Gilley J
(2019)
Low levels of NMNAT2 compromise axon development and survival.
Fricker M
(2018)
Neuronal Cell Death.
Description | BBSRC Industrial Partnership Award |
Amount | £934,853 (GBP) |
Organisation | AstraZeneca |
Department | Astra Zeneca |
Sector | Private |
Country | United States |
Start | 02/2019 |
End | 02/2022 |
Description | Cambridge MRC DTP Industrial CASE (iCASE) Studentship |
Amount | £120,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2023 |
End | 09/2027 |
Description | Establishing causative roles for SARM1 coding and expression level variants in ALS |
Amount | $400,000 (USD) |
Organisation | The ALS Association |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2022 |
End | 02/2024 |
Description | Outreach Award |
Amount | $150,000 (USD) |
Organisation | Thompson Family Foundation Initiative |
Sector | Charity/Non Profit |
Country | United States |
Start | 09/2018 |
End | 09/2020 |
Description | Programmed axon death: a preventable axon degeneration mechanism in some ALS patients |
Amount | $50,000 (USD) |
Organisation | Johns Hopkins University |
Department | The Robert Packard Center for ALS Research at Johns Hopkins |
Sector | Charity/Non Profit |
Country | United States |
Start | 02/2021 |
End | 01/2022 |
Description | Programmed axon death: a preventable axon degeneration mechanism in some ALS patients |
Amount | $50,000 (USD) |
Organisation | Johns Hopkins University |
Department | The Robert Packard Center for ALS Research at Johns Hopkins |
Sector | Charity/Non Profit |
Country | United States |
Start | 02/2022 |
End | 07/2023 |
Description | Wellcome Collaborative Award in Science: Preventable axon degeneration in human disease |
Amount | £3,500,000 (GBP) |
Funding ID | 220906/Z/20/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 03/2026 |
Title | Source data for "Sarm1 Deletion, but Not WldS, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy" |
Description | Source data for figures in associated publication. Each figure panel with analysed data is found as a separate sheet in the excel file. A full descritpion of the datasets and methods can be found in the publication. |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
Description | Collaboration on mechanism and prevention of Wallerian degeneration |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | Basic research into activation mechanism of SARM1 |
Collaborator Contribution | Industrial partnership as part of BBSRC IPA award. Contributes knowledge, discussion, research collaboration, specialised methods such as Mass Spec and chemical synthesis. |
Impact | BBSRC IPA Award |
Start Year | 2017 |
Description | Giuseppe Orsomando |
Organisation | Marche Polytechnic University |
Country | Italy |
Sector | Academic/University |
PI Contribution | Expertise and material from axon degeneration models |
Collaborator Contribution | Expertise in measurement of NAD-related metabolites and enzyme assays |
Impact | Carpi, F.M., Cortese, M., Orsomando, G., Polzonetti, V., Vincenzetti, S., Moreschini, B., Coleman, M.P., and Magni, G. (2018). Simultaneous quantification of nicotinamide mononucleotide and related pyridine compounds in mouse tissues by UHPLC-MS/MS. Sep Sci plus. 1(1):22-30. -- Di Stefano, M., Loreto A., Orsomando, G., Mori V., Zamporlini, F., Hulse, R.P., Webster, J., Donaldson, L.F., Gering, M., Raffaelli, N., Coleman, M.P., Gilley, J., and Conforti L. (2017). NMN deamidase delays Wallerian degeneration and rescues axonal defects caused by NMNAT2 deficiency in vivo. Current Biology. 27(6):784-794 |
Start Year | 2016 |
Description | Prof Richard Piercy |
Organisation | Royal Veterinary College (RVC) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in measuring axonal transport |
Collaborator Contribution | Expertise in equine veterinary science; nerve samples from horses |
Impact | Dr Robert Adalbert will start a two-year collaboration project with Prof Richard Piercy's group in RVC. |
Start Year | 2017 |
Description | Professor Richard Ribchester |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Characterisation of Sarm1/Nmnat-2 double knockout mice with axonal and neuromuscular synaptic protection. |
Collaborator Contribution | Professor Richard Ribchester and his group contributed experimental data derived from muscle tension recordings from knockout mice with axonal and synaptic protection. |
Impact | Gilley, J., Ribchester, R.R., and Coleman, M.P. (2017). Sarm1 deletion, but not WldS, confers lifelong rescue in a mouse model of severe axonopathy. Cell Reports. 21(1):10-16 |
Start Year | 2016 |
Description | 19th Annual Packard Center ALS Research Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Key note speech on the links between Wallerian-like degeneration and various sub-types of ALS and other diseases involving motor axon loss, and also covered what we know about how to stop Wallerian degeneration. |
Year(s) Of Engagement Activity | 2019 |
Description | OPCD Seminar - Oxford |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk titled: Mechanisms of axon degeneration in injury and disease, held at Nuffield Department of Clinical Neurosciences. Level 6, West Wing, John Radcliffe Hospital, Oxford OX3 9DU on September 12th 2019 |
Year(s) Of Engagement Activity | 2019 |
Description | Packard Center PI meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This meeting brings together principal investigators from organisations around the world for discussion and knowledge-sharing. |
Year(s) Of Engagement Activity | 2020,2021 |
Description | Poster presentation at Parkinson's Open-day (Saturday 4th November 2017) |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Dr Andrea Loreto and Prof Coleman poster presentation to Parkinson's patients during the open day organised by Prof Roger Barker's Clinic at the John van Geest Centre for Brain Repair. Poster title: Preventing axon loss caused by mitochondrial dysfunction in Parkinson's disease |
Year(s) Of Engagement Activity | 2017 |
Description | Seminar at Cardiff University Dementia Research Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | I gave a seminar at Cardiff University Dementia Research Institute at the invitation of Owen Peters. |
Year(s) Of Engagement Activity | 2020 |
Description | Seminar at Harvard University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | I presented a seminar at Harvard University at the invitation of Roz Segal. |
Year(s) Of Engagement Activity | 2019 |
Description | Suna Kirac Conference, Istanbul |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I attended and presented at this conference at the invitation of Bob Brown and Nazli Basak. There was an audience of between 100 and 150 people. |
Year(s) Of Engagement Activity | 2019 |
Description | TFFI Retreat |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Brief talk including updates on our current research collaborations. |
Year(s) Of Engagement Activity | 2019 |
Description | Talk at Axon Biology webinar run by ALS Finding A Cure (ALSFAC) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This webinar was focused on Translational Opportunities for Targeting Axonal Degeneration in ALS. There has been substantial progress in delineating new concepts in the molecular biology of axon development, degeneration and regeneration. In parallel there have been exciting advances in understanding the molecular pathophysiology of ALS. The intention for this meeting was to discern how these two areas intersect and thereby define new ways to understand ALS pathophysiology. Thought leaders in the field of axonal biology and ALS, along with new investigators, held extensive discussions to identify new research priorities and projects. |
Year(s) Of Engagement Activity | 2020 |
Description | Talk at Hills Road Sixth Form College, Cambridge |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Presentation to 40 6th form students. Title: The nervous system: the life and death of cells inside your head. |
Year(s) Of Engagement Activity | 2018 |
Description | Univeristy of York Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Seminar speaker at the Univeristy of York, Molecular mechanisms of axon degeneration in injury and disease |
Year(s) Of Engagement Activity | 2019 |
Description | Virtual seminar (Indiana University) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a seminar at the invitation of Hui-Chen Lu, Director and Gill Chair for Linda and Jack Gill Center of Neuroscience, and met with various staff members for discussions, as well as joining their lab meeting. Outcomes were shared learning and ideas. |
Year(s) Of Engagement Activity | 2020 |
Description | Virtual seminar (Presidency University, Kolkata) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a virtual seminar on 'Programmed axon death and its roles in human disease' and held various discussions as a result. |
Year(s) Of Engagement Activity | 2020 |
Description | Virtual seminar (University of Melbourne) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a virtual seminar on 'Programmed axon death and its roles in human disease' at the invitation of Professor Keith Martin and engaged in several discussions afterwards, leading to sharing of information, ideas and plans for future research. |
Year(s) Of Engagement Activity | 2020 |
Description | Virtual seminar at Peking University, Beijing |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | I gave a virtual seminar and engaged in discussions afterwards with others working in fields related to my own, leading to sharing of information and ideas. |
Year(s) Of Engagement Activity | 2020 |
Description | Virtual seminar for Montreal Neurological Institute (Killam Research Seminar) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a virtual Killam Research Seminar at Montreal Neurological Institute, at the invitation of Dr Alyson Fournier. Discussions were held around the seminar, leading to sharing of new plans for research. |
Year(s) Of Engagement Activity | 2020 |