Cosmologist Stephen Hawking is one of the few people who have survived Motor neurone disease. Almost paralysed, he has lived with the disease for about 50 years, trapped in a failing body.
A group of closely related disorders, motor neurone disease affects the nerve cells controlling muscles in the brain and spinal cord, resulting in progressive wasting and weakness because muscles have lost their nerve supply.
In Australia about 1,400 people live with the disease and some 600 die every year. In the US, up to 30,000 are estimated to be living with it. About ten per cent of motor neurone disease (MND) cases are inherited, but only a small proportion has known genetic defects.
La Trobe University has a team of highly regarded scientists, including postdoctoral research officers, PhD, Masters and Honours students, who work on motor neurone disease in Dr Julie Atkin’s Biochemistry Laboratory.
Critical biochemical process
Dr Atkin and colleague Dr Adam Walker recently received between them grants totalling $723,849 from the National Health and Medical Research Council to further their research into this cruel disease. Dr Atkin is probing a critical biochemical process central to motor neurone disease, while Dr Walker has been awarded a four-year overseas-based ‘Early Career Fellowship’ to investigate mechanisms of dementia and motor neuron disease.
‘MND is a cruel disease,’ says Dr Atkin, ‘the cause of which is still unknown. The average length of survival after diagnosis is only 31 months’. A lack of effective therapies, an aging population and projected dramatic increase in neurodegenerative disorders highlights the need for urgent and effective treatment strategies.
She and her team are investigating the underlying biochemical mechanisms in both sporadic and genetic forms of motor neurone disease. Says Dr Atkin: ‘Many new compounds designed to treat motor neuron disease have been tested in clinical trials, all without success. This high failure rate reflects a lack of understanding of the basic biochemical processes involved.’
According to Dr Atkin, motor neurons are unique amongst all other cells, even amongst neurons, because they have unusually high ‘transport’ requirements for cellular maintenance and survival.
Dysfunctional pathway identified
‘We’ve been able to identify that the early part of the cellular secretory pathway is dysfunctional in this disease. So our focus is on directly addressing the biochemical processes causing motor neuron death, a crucial first step towards identifying more effective therapeutic strategies.’
Other studies in her lab include examining a new drug, BMC, for the treatment of motor neurone disease. She says in animal models of the disease, BMC prevents motor neurons from dying. Hence BMC may lead to new treatments for human motor neurone disease.
‘While it is an effective drug, BMC cannot normally enter the brain due to the “blood brain barrier”, a type of filter which prevents some materials from the blood entering the brain,’ says Dr Atkin.
The blood brain barrier, she explains, is a common problem for drugs that have potential to cure neurological disorders. Some materials are able to cross this barrier, for example, those that are soluble in fats. Such drugs can be made to cross the barrier by making them more fat-soluble.
Dr Atkin’s team is collaborating with La Trobe chemist, Dr Peter Barnard, who has synthesised new drugs based on BMC. She says by changing the chemical structure of the drug, Dr Barnard has made new compounds which are more fat-soluble, and hence more likely to cross the blood brain barrier.
‘We are testing the efficacy of these compounds in motor neuron cells and animal disease models, and hope that our research may lead to more effective treatments for motor neurone disease.’
Pursuing abnormal clumps of protein
Dr Adam Walker is using his Early Career Fellowship of more than $300,000 to work for the next two years at the world-renowned Centre for Neurodegenerative Disease Research at the University of Pennsylvania. There he is trying work out the role of a protein, TDP-43, in causing disease.
While the exact causes of motor neurone disease and dementia are not known, Dr Walker says significant progress has been made in recent years.
‘In 2006, Professor Virginia Lee and colleagues at the University of Pennsylvania discovered that a protein known as TDP-43 is a major component of the abnormal protein clumps found in the brains and spinal cords of patients with motor neurone disease.
‘These clumps have also been found in the brains of patients with fronto-temporal dementia which, after Alzheimer’s disease, is the second most common cause of dementia in people under 65 years old, causing behavioural and language dysfunction.
‘These findings show there is significant overlap in the development of motor neurone disease and dementia, however we don’t know how changes in TDP-43 actually cause disease,’ Dr Walker says.
His PhD research, supervised by Dr Atkin’s in her La Trobe lab, focused on the molecular mechanisms involved in motor neurone disease, particularly the endoplasmic reticulum, or ‘ER’, the factory for producing proteins destined for various cell organelles or for export outside of the cell.
‘ER stress occurs when an accumulation of proteins are not ready to ‘export’, resulting in the cell switching on a stress response in order to fix the problem,’ he says.
His work built on earlier findings by Dr Atkin who identified ER stress as a biochemical pathway that is highly activated in motor neurone disease.
‘We showed that a protective protein known as PDI could be a potential therapeutic target in disease,’ he explains. ‘ER stress is an early event in motor neurone disease – and inhibiting this process could be one way of preventing or treating disease.’
Dr Walker says his Fellowship will enable him to learn from world leaders in the field, participate in cutting-edge research, and be of great benefit when he returns to continue his work in Australia. (PU)
La Trobe University motor neurone disease research is supported by the Motor Neuron Research Institute of Australia, the Bethlehem Griffiths Research Foundation and the National Health and Medical Research Council.