Alarm protein sets off international interest

<http://www.sciencealert.com.au/index2.php

Wednesday, 14 November 2007 By Rhonda
Dredge La Trobe University microbiologist Professor Paul Fisher has
discovered that a faulty alarm at the cellular level could be
responsible for many rare and incurable conditions involving
mitochondria – the energy source contained within cells.
The State Government is so impressed by the implications of the La Trobe
research, carried out with PhD student Paul Bokko and others in
Professor Fisher's laboratory, that it has been selected as one of
five Victorian projects promoted in a recent biotechnology push into the
United States.

The Minister for Innovation, Mr John Brumby, announced details of the
new mitochondrial theory at BIO2007 – a biotechnology conference
attracting 19,000 delegates – in Boston in May.

His announcement coincided with scientific publication of the findings
in the international journal Molecular Biology of the Cell.

`Thanks to this research,' Mr Brumby said, `we now have a
completely new understanding of how mitochondrial disease is caused
– from a signalling disorder in the cells, rather than a fundamental
energy insufficiency as was previously thought.'

`The finding has important implications for the development of drug
therapies to treat the many different forms of mitochondrial disease, as
well as for most major neurodegenerative disorders.'

Professor Fisher's research has attracted substantial international
attention, including a piece in the London Financial Times, after the
findings were presented to journalists attending the World Science
Journalists Congress in Melbourne in April.

As a laboratory scientist who has dedicated the last fifteen years of
his life to research on signalling pathways in mitochondrially diseased
cells, Professor Fisher is grateful for the State Government's
support in promoting his work.

He has shown in the laboratory that an energy-sensing protein, known as
AMPK, is permanently activated in mitochondrially diseased cells. When
energy supplies drop, it begins signalling and interfering with other
signalling pathways, causing cell functions to shut down.

So far, Professor Fisher's work has used a type of amoeba called a
slime mould (the scientific name is Dictyostelium discoideum, Dicty to
its friends). Genetically inhibiting the production of the alarm protein
suppressed all of the `symptoms' of mitochondrial disease in
Dicty.

`If we can suppress the symptoms in humans as well, this research
may provide the first possibility of treating mitochondrial
diseases,' Professor Fisher said.

About 1,000 people at any one time suffer from genetic defects of the
mitochondria in Australia, resulting in a varied range of symptoms. More
than 50 children develop these conditions annually and more than half
die before adulthood.

All of the major neurodegenerative diseases such as
Alzheimer's, Huntington's and Parkinson's also involve
mitochondrial defects,' Professor Fisher said. `They might also
be turning on this alarm protein.' AMPK plays a `smoke
alarm' role to censor an impending energy crisis and to take
remedial action.

`If there is an energy problem, the cell does not want to embark on
division or processes that consume energy,' Professor Fisher said.
`So the protein switches them off before the situation becomes
critical.' In healthy cells, energy supplies return to normal, as
does cell functioning, but in diseased cells AMPK activity may trigger a
permanent shut-down.

`In these cases, AMPK acts like an oversensitive smoke alarm that
goes off every time you cook toast. Imagine if it locked every window
and door to stop the fire spreading and turned off the electricity and
gas. This is worse than the problem it tried to solve,' Professor
Fisher said.