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Multiple system atrophy

EXTRA INFORMATION

Understanding why and how MSA occurs

WHAT WE KNOW

About our research

Our aim is to define the pathological pathway that leads to MSA and to identify molecular targets for potential treatment strategies for MSA. Our early research has been instrumental in determining the sequence of pathological events in MSA, which is now recognised as myelin dysregulation (abnormal protein redistributions in oligodendrocytes), followed by demyelination and then neurodegeneration and loss of neurons.

The most common disease that is misdiagnosed as Parkinson’s disease is multiple system atrophy, and both diseases abnormally accumulate the alpha-synuclein protein in their brain. The main difference is that in Parkinson’s disease the protein accumulates in neurons, while in multiple system atrophy it accumulates in their supporting cells, the glia. The Halliday laboratory is trying to understand what underlies these differences.

What we know about MSA:

  • Identified large changes in lipid levels that impact on the glial cells involved.
  • Identified that some people have extremely slow disease progression and are now assessing the factors that seem to arrest the disease in these people.
  • Participated in an international study that suggests the alpha-synuclein protein in MSA may have infectious properties that assists with spreading the disease in the brain.
  • Treatment development and clinical trials.
  • Discovered a new lipid receptor (ABCA8) that is involved.
  • Identified genes involved at the cellular level through transcriptomics.
  • Identified how the pathology spreads in the brain.

Current projects

The glia involved in MSA need sufficient energy to effectively work and support neurons. COQ2 is a gene related to energy production in cells and changes in the COQ2 gene increase the risk for MSA; however, very little is known about levels of expression of this gene, or of the associated energy molecule ATP, in the brain of people with MSA. To establish whether COQ2 activity is indeed a contributing factor in the pathology of MSA, we will measure levels of COQ2 gene and protein in multiple regions of the brain of people with MSA. We will also measure how much of the energy molecule ATP is made. This will help us determine the mechanism of how any deficits in the COQ2 gene contribute to the MSA disease process.

It is possible that boosting the function of COQ2 might combat the disease process of MSA. We will test whether treatment with coenzyme Q10, the product of the COQ2 gene, prevents or reduces alpha-synuclein aggregation in the brain. Using a cell model of MSA, we will measure the effects of different doses of coenzyme Q10 on alpha-synuclein production and aggregation. We expect that coenzyme Q10 treatment will prevent or reduce alpha-synuclein aggregation in oligodendrocytes by ameliorating the levels of ATP and of other molecules known to be involved in MSA pathogenesis. If this approach is successful, we will begin initial therapeutic treatment studies using animal models of MSA.

 

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