Critical function of Kir4.1 for the life-long generation of oligodendrocytes and myelin
Lead Research Organisation:
University of Portsmouth
Department Name: Inst of Biomedical and Biomolecular Sc
Abstract
The massive computing power of the brain depends on the insulation of nerve cell connections with myelin sheaths, by cells known as oligodendrocytes. Bundles of these 'myelinated' connections form the white matter that is very prominent in the human cortex. The loss of myelin is a feature of multiple neuropathologies, most notably Multiple Sclerosis and other demyelinating diseases. However, myelin loss is also important in the poor clinical outcomes of cerebral palsy, stroke, and traumatic injury. Importantly, oligodendrocytes are continuously being lost and regenerated from a pool of stem cells in the brain, called oligodendrocyte progenitor cells (OPCs). These regenerative processes are essential for the life-long maintenance of myelin and for repair of myelin following damage. The failure or impairment of repair results in the loss of myelin and can have devastating effects on brain function. We have identified a key factor that is essential for oligodendrocyte generation, known as Kir4.1 channels. The aim of this project is to determine the importance of Kir4.1 in OPCs in the life-long generation of oligodendrocytes and myelin and maintenance of a healthy brain. This will provide new knowledge on the mechanisms controlling the generation of myelin and how this may go wrong in pathology and may ultimately lead to the identification of new cellular targets for protecting the healthy brain.
Technical Summary
The proposal is to test the hypothesis that Kir4.1 potassium channels expressed by oligodendrocyte progenitor cells (OPCs) are vitally important for the life-long generation of oligodendrocytes and myelin. Oligodendrocytes are specialised to form myelin in the CNS. Myelin is essential for rapid neuronal connectivity throughout the CNS and underlies the massive computing power of the human brain. Moreover, the myelin sheath is essential for the long-term integrity of myelinated axons. Fate-mapping studies in mice provide direct evidence that myelin is replaced throughout life by oligodendrocytes newly generated from endogenous OPCs. The failure of repair has devastating effects on brain function and neuronal integrity in multiple neuropathologies, including multiple sclerosis, leukodystrophies, stroke and traumatic injury. Hence, knowledge of the mechanisms regulating oligodendrogliogenesis in the adult brain are relevant to understanding the life-long maintenance of healthy myelin and potential mechanisms of neuropathology. The applicants provide new evidence of a fundamental role for the inwardly rectifying potassium channel Kir4.1 in oligodendrogliogenesis and myelination in the mouse brain. To take this work forward, we have developed an inducible Cre/LoxP mouse line that targets Kir4.1 specifically in OPCs. These mice provide a major new advance that provides us with the temporal control of Kir4.1 function specifically in OPCs and enables us to determine the importance of Kir4.1 in the control of the regenerative capacity of OPCs in the developing and adult brain and following damage. This is fundamental research that is relevant to multiple neuropathologies and is in line with the MRC Neurosciences and Mental Health Board themes of 'resilience, repair and replacement' and 'living a long and healthy life'.
Planned Impact
The main beneficiaries of the research will be other scientists and clinicians, by providing new knowledge on the mechanisms maintaining a healthy brain throughout life and potential causative factors involved in neuropathophysiology, with particular relevance to multiple sclerosis and other demyelinating diseases.
This research will also be of interest to patient groups, and the wider public. This project will fill an important gap in our knowledge on promoting a healthy brain across the life-course. We will use several routes to engage potential user groups and the general public, by open lab visits to the general public, presenting to local schools, writing articles for magazines, and presenting to the public and patient groups at meetings of Portsmouth MS Society, University of Portsmouth Ageing Network (UPAN), Alzheimer's Research UK (ARUK) Southern Network.
It is not anticipated that any direct commercial benefit will arise from this project, but the longer term plan is to use the information gained in this research to identify new potential therapeutic targets for promoting 'resilience, repair and replacement' in the brain and 'living a long and healthy life', which would ultimately enhance the quality of life and health and have considerable economic benefit.
This research will also be of interest to patient groups, and the wider public. This project will fill an important gap in our knowledge on promoting a healthy brain across the life-course. We will use several routes to engage potential user groups and the general public, by open lab visits to the general public, presenting to local schools, writing articles for magazines, and presenting to the public and patient groups at meetings of Portsmouth MS Society, University of Portsmouth Ageing Network (UPAN), Alzheimer's Research UK (ARUK) Southern Network.
It is not anticipated that any direct commercial benefit will arise from this project, but the longer term plan is to use the information gained in this research to identify new potential therapeutic targets for promoting 'resilience, repair and replacement' in the brain and 'living a long and healthy life', which would ultimately enhance the quality of life and health and have considerable economic benefit.
People |
ORCID iD |
Arthur Butt (Principal Investigator) | |
Anthony Lewis (Co-Investigator) |
Publications
Brasko C
(2017)
Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS.
in Brain structure & function
Butt AM
(2022)
Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain.
in Cells
Chacon-De-La-Rocha I
(2020)
Accelerated Dystrophy and Decay of Oligodendrocyte Precursor Cells in the APP/PS1 Model of Alzheimer's-Like Pathology.
in Frontiers in cellular neuroscience
Chacon-De-La-Rocha I
(2021)
The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus.
in Journal of neuroscience research
Ferreira R
(2023)
Amburana cearensis seed extract stimulates astrocyte glutamate homeostatic mechanisms in hippocampal brain slices and protects oligodendrocytes against ischemia
in BMC Complementary Medicine and Therapies
Papanikolaou M
(2019)
Glial and neuronal expression of the Inward Rectifying Potassium Channel Kir7.1 in the adult mouse brain.
in Journal of anatomy
Papanikolaou M
(2020)
A critical role for the inward rectifying potassium channel Kir7.1 in oligodendrocytes of the mouse optic nerve.
in Brain structure & function
Rivera AD
(2022)
Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination.
in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Rivera AD
(2022)
Resolving the age-related decline in central nervous system myelin turnover and drug discovery for oligodendroglial rejuvenation.
in Neural regeneration research
Rivera AD
(2021)
Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors.
in Pflugers Archiv : European journal of physiology
Rivera AD
(2022)
Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration.
in Frontiers in cellular neuroscience
Vanzulli I
(2020)
Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease.
in Neurobiology of aging
Title | Aging mouse oligodendrocyte progenitor cells |
Description | Microarray dataset |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The data was published in a paper |
Description | Olivier Raineteau, INSERM, Lyons |
Organisation | École normale supérieure de Lyon (ENS Lyon) |
Department | INSERM U846 (Stem-cell and Brain Research Institute) |
Country | France |
Sector | Public |
PI Contribution | Experimental design, hosting researchers, writing and publishing papers |
Collaborator Contribution | Experimental design, hosting researchers, writing and publishing papers |
Impact | Publications |
Start Year | 2017 |
Description | Southampton University |
Organisation | University of Southampton |
Department | Southampton Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Data production and analysis, experimental design, paper writing |
Collaborator Contribution | Provision of tissue, analysis, design, writing |
Impact | Two publications and presentations at meetings |
Start Year | 2017 |
Description | Bahia Brazil Neurochemistry Workshop Oct-10-2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Glial meeting in Salvador Brazil |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The PDRA Dr Andrea Rivera was invited to present our data at a Glial meeting in Salvador Brazil, which sparked questions and lively discussions, leading to collaborations. |
Year(s) Of Engagement Activity | 2017 |
Description | IoP Lectures |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Oral presentation that sparked questions and discussions |
Year(s) Of Engagement Activity | 2019 |
Description | Italy, Aqua Therme May 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Public meeting on brain health during ageing, resulting in lively discussions and the plan to organise a larger meeting in 2018. |
Year(s) Of Engagement Activity | 2017 |
Description | King's College Lectures |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | Oral presentation that sparked questions and discussions |
Year(s) Of Engagement Activity | 2019 |
Description | Meeting in Padua, Italy, Nov-25-2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussions resulting in future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Meeting in Prague, Czech Republic March-4-2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussions for future collaborations |
Year(s) Of Engagement Activity | 2020 |
Description | Milan University Dec 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Presentation to potential research collaborators, which sparked a new collaboration. |
Year(s) Of Engagement Activity | 2017 |
Description | NUDZ Prague Sep-19-2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Neuroglia Meeting Lubjana, Slovenia Nov-7-2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Neuroglia Meeting Tblisi, Georgia Sep-27-2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Paris Boris Zalc March-13-2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussions and future collaborations |
Year(s) Of Engagement Activity | 2020 |
Description | Paris meeting with Kaz, Olivier and Carlos Sep-10-2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Pint of Science 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Public talk in pub, generated questions and discussions. |
Year(s) Of Engagement Activity | 2019 |
Description | Public Talk, Connelli, Italy |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Public Talk in Connelli, Italy, on our work focusing on maintaining a healthy brain across the lifecourse. Over 100 people attended the talk, ranging from general public to local and national politicians and media. |
Year(s) Of Engagement Activity | 2018 |
Description | Purine Meeting, Santiago, Spain Sep-5-2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Signalling meeting, Limerick, Ireland Nov-13-2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | Strasbourg Brain Ageing Conference March-16-2020 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2020 |
Description | Turin University and Medical School, Dec 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talks with potential collaborators that sparked discussions and potential for collaborative research. |
Year(s) Of Engagement Activity | 2017 |
Description | Visit Christine Rose Germany |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Talk with Christine Rose group and exchange of ideas and arrange future lab visits |
Year(s) Of Engagement Activity | 2016 |
Description | Visits by Silvia Lima Costa and Suzanna Braga July-Aug 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Brazilian colleagues visited my labs and we held a workshop for the exchange of ideas, resulting in lively discussions and future collaborations. |
Year(s) Of Engagement Activity | 2017 |
Description | Workshop Portsmouth-Bahia, Brazil July 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentations that sparked questions and discussions and future collaborations |
Year(s) Of Engagement Activity | 2019 |
Description | iBrain Lecture University of Dusseldorf |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Presentation of new data on brain ageing and pharmaceutical interventions, which sparked questions and discussions afterwards. |
Year(s) Of Engagement Activity | 2017 |