Mutants and mitochondria: from accident to medical breakthrough

In the 90s, Professor Paul Fisher and his team of La Trobe University scientists were making ‘mutants’ from a simple model organism. But this isn’t an X-Men-style sci-fi thriller (what scientists call a ‘mutant’ is just the result of an altered gene), although the outcome has caused a stir. The La Trobe mutant has led to a blood test that could enable early treatment of Parkinson’s disease.

Benefits of early diagnosis

An estimated 70,000 Australians and 6.3 million people worldwide suffer from Parkinson’s, a progressive neurodegenerative condition affecting movement and mobility.

Until a patient starts showing clinical symptoms, it can be extremely difficult to detect the disease. Currently, the only method is neurological examination, which is fraught with problems.

‘It could take a decade or more to finally arrive at the correct diagnosis,’ says Professor Fisher, ‘which is a decade or more a patient may not be receiving the right treatment. By the time patients develop enough symptoms for a definite diagnosis by a skilled neurologist, large numbers of vital brain cells have already been destroyed.’

Professor Fisher says early diagnosis of Parkinson’s could lead to early treatment – symptoms can then be managed with the right medication.

According to Professor Fisher, early diagnosis could lead to early treatment of Parkinson’s, which is vital, given the symptoms can often be managed with the right medication.

‘The disease will still progress over time and eventually take its toll,’ he says, ‘but in the meantime the quality of life can be improved a lot with these treatments.’

A call to arms

Flashback to the 90s: Professor Fisher's team were making ‘mutants’ from a simple model organism. They were involved in a search for genes that could sense light, but to their shock, the mutant turned out to have a mitochondrial disease.

Mitochondrial disease affects the mitochondria, which generate the energy our muscle fibres, brain and blood cells need to function.

When we’re running low on energy, we feel lethargic and hungry. Our bodies try to fix the energy deficit by rationing energy expenditure and demanding food with increasing urgency until we fuel up.

Our cells work much the same way.

‘There’s a sort of cellular alarm protein that senses how the cell is going in terms of its energy supply,’ Professor Fisher explains. ‘If a protein needed for mitochondrial energy production is damaged, that means the cell can’t make as much energy quickly and the alarm protein gets activated.’

Usually, this would be a call to arms: the cell would lower its consumption of energy and tell its mitochondria to get busy producing more energy. Under normal circumstances, this process would solve your energy crisis.

But when there is a genetic defect affecting the mitochondria, the usually efficient chain of supply and demand is permanently disrupted and the cell’s alarm protein never switches off.

When they saw this play out in their mitochondrial mutants, Professor Fisher and collaborators Dr Danuta Loesch and Dr Sarah Annesley wondered if the same alarm protein was involved in human brain diseases. According to available scientific research, Alzheimer’s, Huntington’s, Motor Neurone and Parkinson’s disease all involve a mitochondrial defect.

What they found instead in cultured blood cells from Parkinson’s patients was another shock. Instead of being defective, the mitochondria from patients were functionally normal but hyperactive.

Diagnosing with clarity

The theory is that this increased mitochondrial activity in cells leads to mitochondrial damage in the brain, which would then be a by-product of Parkinson’s and not the cause of it.

This is where Professor Fisher’s blood test could deliver major advantages. The test can clearly distinguish between patient groups and control groups, which is important because ‘the difference between the Parkinson’s white blood cells and the healthy control white blood cells is very dramatic. We saw an increase of about four fold in mitochondrial activity in our pilot study.’

For that study, the La Trobe team and collaborators at other institutions looked at a group of patients diagnosed with Parkinson’s. Their ages ranged from the 30s to the 80s, and the post-diagnosis range was two years to more than 25 years. There were 30 patients in the study and 9 healthy control subjects, and using this test, he says, ‘we would have misdiagnosed only one. One of those controls fell into the bottom end of the range for the Parkinson’s group – so that’s actually a really unprecedented level of reliability’.

Towards the future

While the research team has made incredible progress, the blood test isn’t ready for the public just yet.

‘Apart from verifying our findings in a larger cohort of individuals, there are a number of questions we still have to answer,’ says Professor Fisher. ‘The first is how specific this increased mitochondrial activity is to Parkinson’s disease, as opposed to the other brain diseases. We have already found evidence that this also happens in a rare brain disease called FXTAS: Fragile X-associated Tremor and Ataxia. The second is how early we can detect Parkinson’s in a patient. With enough funding, we could do those studies quite quickly.’

Professor Fisher’s test distinguishes between Parkinson’s white blood cells and the healthy cells of control subjects. That gives unprecedented reliability.

Despite the challenges, the broader implications are extremely promising.

‘If what we’re finding in the patients’ blood cells applies also to the brain cells, then the mechanism for the disease is different,’ he says. ‘That could lead to new treatments.’

Whatever those new treatments may be, the research is changing our understanding of how the disease works. And through early diagnosis, that has the potential to greatly improve people’s lives.

Professor Paul Fisher is Professor of Microbiology and Head of Discipline of Microbiology, La Trobe University.

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