Understanding the oligodendrocyte death in the CNS

Dr Tobias D. Merson

Florey Neuroscience Institutes

| A cure via repair and regeneration | Neurobiology | Project | 2009 | Investigator Led Research |
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Summary

Oligodendrocytes are the cells in the central nervous system (CNS) that produce myelin. In Multiple Sclerosis (MS), oligodendrocytes are damaged and myelin that normally insulates the axons of nerve cells is lost, a process known as demyelination. When nerve cells become demyelinated due to oligodendrocyte death they become dysfunctional. This project aims to define the response of neural and immune cells to oligodendrocyte death in the brain. Using a novel model that enables the specific induction of oligodendrocyte death we will define the response to oligodendrocyte death to understand the earliest events in human MS.

The underlying cause of MS is unknown and current animal models reflect only certain aspects of the human disease. Recent data indicate that the earliest pathological event in at least a subpopulation of human MS lesions is oligodendrocyte apoptosis. It has been postulated that oligodendrocyte apoptosis may activate a cascade of neuroinflammatory events leading to the induction of an autoimmune response targeted against oligodendrocytes and myelin. It remains highly debated whether oligodendrocyte apoptosis per se could be a precursor to a secondary immune response that results in progressive inflammatory demyelination, a controversy that demands intensive experimental investigation.

We have generated transgenic mice that enable the specific induction of oligodendrocyte apoptosis in vivo. The mice express the human Diphtheria Toxin Receptor (DTR) under the regulatory control of the mouse Myelin Basic Protein (MBP) promoter. Following systemic administration of diphtheria toxin to MBP-DTR mice, oligodendrocytes undergo apoptosis, resulting in demyelination of white matter tracts in the CNS. MBP-DTR mice will be used to dissect the specific response of neural and immune cells to oligodendrocyte apoptosis. The understanding that will be gained from these experiments will enable us to address whether oligodendrocyte apoptosis is sufficient to induce a secondary inflammatory disease and whether this can potentiate autoimmunity.

Progress to Date

This project aims to understand how precursor cells become activated to replace oligodendrocytes that are destroyed in the central nervous system of patients with Multiple Sclerosis (MS). Although regeneration of oligodendrocytes occurs spontaneously in MS, this becomes limited as disease progresses, resulting in permanent damage of nerve cells. By understanding this repair process the aim is to understand how to target precursor cells to enhance repair.

Oligodendrocytes are the cells in the central nervous system (CNS) that produce myelin. In diseases such as Multiple Sclerosis, oligodendrocytes are damaged and myelin that normally insulates the axons of nerve cells is lost, a process known as demyelination. When nerve cells become demyelinated due to oligodendrocyte death they become dysfunctional. Scientists use the term ‘apoptosis’ for cell death.

This project aims to define the response of neural and immune cells to oligodendrocyte death in the brain. Using a novel model that enables the specific induction of oligodendrocyte death we will define the response to oligodendrocyte death to understand the earliest events in human MS.

The project had 6 distinct aims and Dr Merson has been successful in achieving results and conclusions for each of these aims. The research has been very productive and revealed critical new information on the disease causing processes that occur subsequent to oligodendrocyte apoptosis. Moreover the research has drawn significant interest from national and international groups working on similar research.

The researchers have made significant breakthroughs using a mouse model of MS called the MBP-DTR mouse model. These findings have revised the scientific community’s understanding of the body’s response to oligodendrocyte apoptosis and the subtle mechanisms occurring oligodendrocyte/axon interface. In particular the observation of acute axonal injury prior to evidence of frank demyelination indicates that oligodendrocyte-associated induction of neuronal pathology could proceed in the absence of demyelination.

These findings could have significant impact in understanding the pathogenic mechanisms operative within MS lesions that appear otherwise normally myelinated and highlights the requirement to assess pathological specimens for more subtle changes at Nodes of Ranvier that could be indicative of early pathogenic processes reflecting primary oligodendrocyte dysfunction or death.

This work has resulted in a number of publications in scientific, peer-reviewed journals.

Publications

Merson TD, Binder MD, Kilpatrick TJ (2010) Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Medicine 12(2):99-132.

Oluich LJ, Stratton JAS, Xing YL, Ng SW, Cate HS, Sah P, Windels F, Kilpatrick TJ, Merson TD. Targeted ablation of oligodendrocytes induces axonal pathology independent of demyelination. Journal of Neuroscience J Neurosci. 2012 Jun 13;32(24):8317-30

Xing YL, Röth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, Ng SW, Kilpatrick TJ, Merson TD Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. Journal of Neuroscience 2014 Oct 15;34(42):14128-46. doi: 10.1523/JNEUROSCI.3491-13.2014.

Updated: 22/10/2014

Updated: 06 January, 2009

Co-investigator

Grant Awarded

  • Project grant

Total Funding

  • $100,000

Duration

  • 2 years

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Understanding the oligodendrocyte death in the CNS