Two reports published simultaneously in the journal Science on 27 February 2009 describe mutations that have been identified in the gene encoding fused in sarcoma (FUS). One study describes FUS mutations found in Australian and UK MND families; the other reports FUS mutations in North American MND families.

FUS mutations account for between 3% and 5% of MND families. As such, FUS is the second most common known cause of MND after SOD1. However, a substantial significance of this discovery lies in the functional similarity of the FUS protein with TDP-43, a protein previously shown to be abnormal in MND. Abnormal TDP-43 pathology is thought to be present in over 90% of all MND cases (sporadic and familial MND combined). In contrast, SOD1 pathology only accounts for about 2% of all MND cases.

Until now, the known MND genes (including SOD1, TDP-43 and ANG) had diverse and seemingly unrelated functions. It has been difficult to identify a common defective mechanism underlying motor neurone degeneration.

With the discovery of abnormal FUS in MND, a common defective mechanism has been identified. Both FUS and TDP-43 are RNA binding proteins that are thought to process and transport RNA. They both normally reside in the nucleus of the cell. In the affected motor neurones of most MND patients, TDP-43 is shuttled out of the nucleus to the cytoplasm where it forms aggregates. This same process has been found to occur with FUS in MND patients who carry a FUS mutation.

Research efforts can now focus on this common defective mechanism to better understand the disease biology and ultimately give insights into new therapies that target that defective process. Development of cell and animal models based upon mutant FUS should help accelerate the search for therapies.

This work was made possible by the dedicated cooperation of families with inherited MND. In Australia, the work was supported by the National Health & Medical Research Council and the Peter Stearne Grant for Familial MND from the MND Research Institute of Australia.  

Source: International MND research update – March 2009, Dr Ian P Blair and Professor Garth Nicholson ANZAC Research Institute & University of Sydney for MNDRIA


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