Motor Neuron Disease (MND/ALS)
The motor neurons are nerves that extend from the brain to the muscles and provide the stimulus through which we move, breathe, eat and drink. The motor neuron diseases (MND) are a group of related neurodegenerative diseases that cause the progressive death of motor neurons. These diseases range from rare slowly progressive, non-fatal forms to the rapidly progressive fatal disorder amyotrophic lateral sclerosis (ALS). ALS is the most common form of MND. ALS typically leads to death within 3 to 5 years of first symptoms. The main feature of ALS is muscle denervation that gradually worsens. Initially the hands and arms, or feet and legs are affected. Symptoms worsen and spread to involve many muscles in the body. While muscles atrophy, intellect and senses usually remain intact, although a proportion of cases develop subclinical and clinical frontotemporal dementia. The cause of death is usually respiratory failure and pneumonia. The hereditary motor neuropathies (HMN) are a group of slowly progressive non-fatal MNDs that lead to severe lifelong disability.
The prevalence of MND in the overall population is around 5 to 10 per 100,000. However, few cases exist under age 50. We estimate the prevalence among Australian’s over 50 is around 1 per 5,000. About 1,300 Australians currently suffer from MND. The prevalence worldwide is similar, with over 300 cases diagnosed every day.
Our MND/ALS research team
Dr Ian Blair, Dr Shu Yang, Carolyn Cecere, Jennifer Durnall, Alexander Drew, Kelly Williams, Annora Thoeng, Sadaf Warraich, Jennifer Solski, Prof Garth Nicholson
Family studies and genetic analysis of MND/ALS
Our MND/ALS research team at the Northcott Neuroscience Laboratory at the ANZAC Research Institute in Sydney has recruited MND families for over 10 years. These have been identified through our close association with neurogenetic clinics and through our role as a referral centre for SOD1 DNA diagnostic testing. Our current MND family cohort stands as one of the largest worldwide.
MND family recruitment
We are actively recuiting MND families and family members for our research. If you or your family are interested in participating in our research, please contact Carolyn Cecere at ccecere@anzac.edu.au or (02) 9767 7016.
There is no specific test for the diagnosis of MND and treatment is extremely limited. The only known causes of MND are mutations in particular genes that lead to death of motor neurons. The known MND genes only account for about 2% of all cases. The goal of our research is to gain an understanding of the biological basis of MND through identification of defective genes that cause the death of motor neurons seen in both ALS and non-ALS MND. This understanding is a prerequisite to effective diagnosis, treatment and prevention of MND.
The causative disease genes remain to be identified in most MND families. We have commenced genome-wide genetic linkage scans among families within our cohort in an effort to determine the chromosomal location of new disease genes. This work has led to the following projects.
Mutations in TDP-43 cause MND/ALS
Recently reported studies have identified a protein (TDP-43) that aggregates in the degenerating motor neurons of almost all MND/ALS patients. In collaboration with Prof Christopher Shaw's research group at Kings College London, we have identified mutations in the gene that encodes TDP-43 in familial and sporadic MND/ALS patients (Sreedharan et al 2008). This establishes for the first time a clear role for TDP-43 in the disease. This is an exciting finding that will initiate a new chapter in MND/ALS research. It offers a unique opportunity to determine the mechanism by which mutant TDP-43 leads to motor neuron loss. This will have crucial and direct implications for understanding how motor neurons degenerate in MND/ALS as a whole. Our research is now focusing on how these mutations act to cause disease.
The long-term aim of our research is to identify and investigate the biology of those genes that either cause or predispose to ALS. Based upon our preliminary studies, we hypothesise that mutations in TDP-43 cause ALS. The aims of our current TDP-43 related research are to:
- Further investigate the pathogenic role of the gene encoding TDP-43 among extended ALS patient cohorts.
- Investigate the functional consequences of TDP-43 mutations in patient cells.
- Establish neuronal cell and animal models expressing mutant TDP-43 to investigate the functional consequences of identified mutations.
Mutations in FUS cause MND/ALS
In collaboration with Prof Christopher Shaw's research group at Kings College London, mutations in the gene FUS have been identified in Australian MND/ALS families who are participating in our research (Vance et al 2009). FUS is closely related in function to TDP-43 and discovery of FUS mutations in ALS eludes to a common pathogenic mechanism in motor neuron degeneration. This is another exciting finding that will lead to the development of cell and animal models of the disease and should help accelerate efforts to identify treatments. As with our TDP-43 research, our research is now focusing on how FUS mutations act to cause MND/ALS.
A new MND gene on chromosome 7
We have identified a region on chromosome 7 that harbours a previously unidentified motor neuron disease gene (Gopinath et al 2007). Work is now underway to narrow the chromosomal interval and isolate the gene in question. Once identified, this new gene can be tested among other MND families. Work can also commence to determine the biological role of the defective gene, which we expect to provide substantial insight into the cause of the disease.
A search for new MND/ALS genes
We are performing genome scans among multigenerational MND/ALS families to identify chromosomal regions containing previously unknown MND/ALS disease genes.
Investigation of known MND/ALS genes
We are investigating known MND/ALS genes and the functional consequences of previously unknown disease causing mutations. Molecular and cell biology approaches will be used to generate and investigate cell culture models and the mechanisms and pathways that lead to motor neuron death.
Identification of one or more of these new MND/ALS genes will provide vital clues to the biological pathways leading to premature death of motor neurons seen in both familial and sporadic cases of MND/ALS. We envisage that this will lead to the development of new drugs to prevent and treat these devastating disorders.
