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A study of how increased copper may be harmful in Amyotrophic Lateral Sclerosis


Mental Health Research Institute

Year Of Grant:



Motor Neuron Disease,


James Duce


The original proposed project was for 2 years of funding. The board of reviewers at BGRF were only able to fund for 1 year but it was strongly recommended that additional funding for the 2nd year should be asked for in the future. This is what we have successfully done and therefore the project has continued into 2010. The original aims to the proposal were:
Aim 1. To genetically increase copper by co-expression of the copper transporter hCTR1 with mutant G93A or wild-type human SOD1 (N1029) transgenic mice and study the progression of motor dysfunction.

Aim 2. To biochemically determine if the increased copper concentration results in an increase in toxicity and thus pathology within the spinal cord compared to other tissue.

While these aims have not fully been achieved to date, we believe we have met our mid-term targets and thus should fulfill the proposed aims within the initially proposed time of 2 years. The mid-term targets we have successfully met are:

1.We have received from Jackson Laboratories breeding pairs of mice containing high copy numbers of wild-type human SOD1 (B6SJL, N1029) or the G93A human SOD1 mutation (B6SJL-TgN (SOD1-G93A)1 Gur). These have been used to set up successful colonies within our animal house.
2.We have received the hCTR1 transgenic breeding pairs of mice from our collaborators at Deakin University, Burwood, Victoria. Again, these have been used to set up successful colonies within our animal house.
3.hCTR1 transgenic mice have successfully been crossed with SOD1 transgenic mice either containing the wild-type human SOD1 or the G93A human SOD1 mutation.
4.A Technical Assistant with animal experience has been employed to specifically work on this project.
5.hCTR1xWT-SOD1 mice are currently undergoing behavioural testing using the Rotorod to study the progression of motor dysfunction. Comparisons are being drawn with the single transgenic littermates.
6.Spinal cord and other tissue have been collected and stored from hCTR1xWT-SOD1 and hCTR1xG93A-SOD1 mice at various ages for biochemical analysis in the near future.


As explained above, this project was originally described as a 2-year proposal. Therefore data collated from funding received in 2009 is at too early a stage for publication or presentation. It is expected that future publications will arise once the full 2-years of funding from BGRF has been reached.


2-3% of Amyotrophic Lateral Sclerosis (ALS) cases are caused by a mutation to the enzyme copper, zinc-superoxide dismutase (SOD). How mutations in the SOD gene sequence cause ALS remains a topic of debate. However, there is growing evidence that the way SOD uses the metals copper and zinc may be involved in causing the disease. One such line of evidence is the observation that decreasing the amount of copper in the body can extend the life span in mouse model that presents ALS symptoms. To support this theory we set out to study if increasing copper in the spinal cord in these mouse models, containing an ALS-related mutation in SOD, could exacerbate the progression of the disease. We are currently only partially through the 2-years BGRF supported project, but early indications have shown that we are able to use our model system to test if metals are important in the disease. The completion of the proposed project will expand on the valuable information already collected this year describing the relationship of copper and SOD in disease progression. The spurious copper bound to SOD could represent a new target for future drug design and our new mouse model would provide a system to test pharmacological agents for their potential to ameliorate the effects of increased copper.

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