Basic Sciences

Introducing the Basic Sciences Team

Our third Melbourne Brain Centre Feature Week focussed on the research being undertaken by their Basic Sciences team.  To kick things off, Professor Trevor Kilpatrick, Director of the Melbourne Neuroscience Institute, introduced the team, explaining the origins of the group, their goals and how and why they are well-positioned to provide much needed information about the causes of multiple sclerosis.

Professor Kilpatrick’s high-level introduction was complemented by the following research summaries, provided by Dr Melissa Gresle and Gerry Ma.  As well as give an insight into the work being undertaken by the team, these summaries provided the basis for Thursday’s Google Hangout.

A NEW MARKER TO PREDICT MS PROGRESSION

When people are diagnosed with MS, it is very difficult to predict how their condition will progress as each individual will often have different outcomes. This leads to a large level of uncertainty for the person involved. Recently however, it has become apparent that the level of damage to axons does correspond to disability progression. Therefore, there is a lot of current work that is focused on developing an easy clinical technique for assessing this axonal injury, which could be used to more accurately predict or monitor an individual’s MS.

It is known that a major part of the axon is made up of three parts, known as neurofilament subunits, of which there are the heavy, medium and light subunits. Previous work has shown that after axonal injury or death, these subunits can be detected in both the serum and cerebrospinal fluid (CSF). In addition, high levels of both the light and heavy neurofilaments in the CSF are associated with poorer clinical outcomes. Due to the dangers and invasiveness of lumbar punctures, a marker present in serum would be better than having to analyse CSF.

In this study by Gresle et al, the use of a modified (phosphorylated) form of the heavy subunit was assessed as a potential marker of disease progression. The levels of this protein were studied in people with relapsing-remitting MS (RRMS – 81), secondary progressive MS (SPMS – 13), primary progressive MS (PPMS – 6), as well as those with a first demyelinating event (FDE – 82) and unaffected individuals (135). The protein was found in the serum of 9% of people with RRMS and FDE, as well as 38.5% with SPMS. Furthermore, they showed that high levels of this protein in the serum matched to worse disease progression. Therefore, the use of a blood test to assess the levels of the phosphorylated heavy neurofilament subunit may be useful to accurately predict and monitor MS progression.

The full text of this article can be found in the J Neurol Neurosurg Psychiatry, March 2014.

IDENTIFYING A NEW SUSCEPTIBILITY GENE IN MS

The loss of myelin from nerves (demyelination) is a key feature of multiple sclerosis. However, the mechanisms that result in this process are still not well understood. It has been shown previously in both animal models and people with MS that a family of proteins, known as the TAM family, may play a role in demyelination. It is thought that this may occur through modulation of the immune system and increasing the survival of myelinating cells.

To investigate the association of the TAM genes in MS, Ma et al sought to identify single-nucleotide polymorphisms (SNPs – small variations found within genes) in a group of 1618 people with MS and 3414 healthy controls. Using this approach, a number of SNPs were identified in one of the TAM family genes, known as MERTK, which appeared to associate with MS. To increase the power of the findings, the study was replicated in a second group, this time with 1140 people with MS and 1140 healthy controls. It was shown that 12 of the variations were discovered again, thus strengthening the case for their association with MS. Furthermore, these variations appear to be inherited together, indicating that MERTK could be a novel risk gene for MS susceptibility. Understanding the role of MERTK will provide new insights into the process of demyelination and potentially lead to new, targeted therapeutics to combat this.

To complement this second summary, Professor Kilpatrick presented a follow up video further explaining how the MERTK gene was identified, what research is currently being done on it and what this might mean in the future for potential new treatments of MS.

Our final features for the week were two videos presented by Associate Professor Helmut Butzkueven.  The first discussed the importance of understanding the genetics of multiple sclerosis, while the second introduced the genotype/phenotype study currently being undertaken, explaining how genetic markers can be used to predict outcomes of multiple sclerosis.