Protein switch identified in connection with disability progression in MS

Dr. Jacqueline Quandt outside of the Djavad Mowafaghian Centre for Brain Health.

Pictured: Dr. Jacqueline Quandt. Image credit: Paul Joseph/UBC.

Researchers know that the loss of neurons and their axons is responsible for disability in multiple sclerosis (MS), and inflammation associated with immune cells is thought to be implicated in this process. But to truly understand how the brain’s cells are affected by oxidative stress, researchers led by Dr. Jacqueline Quandt have been looking closely at the mechanisms behind this immune-mediated degeneration. Recently, with the support of the MS Society of Canada and a cadre of local philanthropists, Dr. Quandt has been able to look at parts of the neuronal network in models of MS in greater detail than ever before.

Dr. Quandt and her team, including Pierre Becquart and graduate student Tissa Rahim, have identified a neuroprotective protein that, when lost  in an inflammatory setting, may act as a switch between disease progression and processes of repair in MS. The researchers examined the role of ARNT2 (also known as aryl-hydrocarbon receptor nuclear translocator 2), a protein that is responsible for maintaining healthy neurons. ARNT2 is associated with neural growth and development; when the protein is lacking, the brain does not develop normally and results in birth defects and shorter lifespans. ARNT2 is known to be an important contributor to the survival of cells, but its role in central nervous system diseases like MS has not been well understood.

Dr. Quandt’s team evaluated ARNT2 levels in mouse models of MS across the disease course, and found that at the peak of disability, up to 80 per cent of the protein was gone in spinal cord neurons. They also found that ARNT2 expression is tied to brain-derived neurotrophic factor (BDNF), a protein that also supports brain cell survival and growth; . Recovery is associated with the return of ARNT2 expression.

“This is the first time that we’ve implicated this protein combination in neuronal survival and health,” says Dr. Quandt. “We see that the ability of the brain’s cells to thrive is really dependent on this protein, and that it is perhaps one of the mechanism driving the balance between neurodegeneration and repair processes in disorders such as MS.”

The team found that ARNT2 is particularly vulnerable to oxidative stress caused by immune cells. And while it is still early to say whether or not reducing inflammation to protect ARNT2 is the critical step, this is the first time researchers have been able to identify this protein as a mediator in a cascade of problems associated with oxidative stress in a disease model.

The novelty of these findings is significant, and was enabled by the generous support of a collective of anonymous donors through the VGH & UBC Hospital Foundation. “The equipment was absolutely fundamental to this discovery,” explains Dr. Quandt. “Using this fluorescence microscope and biochamber funded by a group of donors, we were able to look more closely at what is happening in the brain at the cellular level, and see in far more detail than we could otherwise what is happening when oxidative stress triggers changes in cell proteins.”

Dr. Quandt’s findings are part of a research study to identify novel factors and pathways associated with disease onset and progression in MS and models of MS. She will also contribute to CanProCo, an upcoming longitudinal study funded by the MS Society of Canada and Brain Canada by providing an immunologists’ perspective, particularly related to immune-mediated responses that contribute to progression in MS.

Citation

 Rahim, TR; Becquart, T; Baeva, ME; Quandt, J. Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis. Journal of Neuroinflammation, 2018.