“The gift that
keeps on taking” someone called it. It starts with a little twitching that you
think it will go away, but instead grows and soon your limbs shake, your balance
and coordination lost. Parkinson’s disease (PD) affects almost 10 million
people worldwide, but many more still undiagnosed until their symptoms
emerge often years into the disease. It is also incurable.
But the discovery that PD can have a genetic cause – until recently the only known triggers were
environmental– brought new hope. This because once the function of the faulty
gene is identified, it should be easier to pinpoint where things have gone
wrong. DJ-1 is a particularly interesting example, a gene that causes several
forms of PD, but is also linked to cancer, Alzheimer’s and other
neurodegenerative diseases, suggesting it plays an important role in the protection
against the effects of ageing.
And in fact, a study just out in the journal PNAS by scientists in Portugal, Germany
and the UK have found that in yeast - a common model to study human genes –
deleting DJ-1 from the genome disrupts several cellular protective mechanisms
and, ultimately, the yeast’s survival.
Even more important, Miller-Fleming, Outeiro, Giorgini and colleagues
found where the yeast’s DJ-1 “steps in” – it modulates a protein called TORC1, which regulates ageing by managing the
balance between protein formation and destruction, suggesting that this
molecule could be a key to PD.
But with the work done in yeast will the results be relevant to humans?
Anomalies in TORC1 levels seen in cancer and neurodegenerative diseases suggest
that the answer is yes. If the results can in fact be repeated in human neurons
(the researchers’ next step), this would see TORC1 (and DJ-1) as targets for
potential novel therapies against PD and cancer, where DJ-1 also plays an
important role. The study is to be published in the journal PNAS and comes from the Instituto
de Medicina Molecular, Lisbon, the University Medical Center Goettingen and the
University of Leicester.
PD is unique
among neurodegenerative diseases because, although we do not known what
provokes the neuronal death that leads to disease, we do understand a great
deal about the progression of the typical motor symptoms, which are caused by the
loss of dopaminergic neurons (producing dopamine, a chemical messenger) in a brain area linked to movement
called substantia nigra. As the destruction spreads to other areas of the brain, the
patients develop cognitive and behavioural problems and, ultimately, dementia.
Without knowing what causes the neural death, all that currents treatments (usually
dopamine replacements) can do is mask the motor symptoms, but even this, as the
disease progresses and more neurons die, stops working. Ultimately, there is
nothing that can stop PD brain destruction.
Three things, thought, seem to be constant across all
different forms of PD; the affected neurons have abnormal deposits of proteins,
malfunctioning mitochondria (the
cells’ energy-producing “factories”), and show signs of oxidative stress (when there is build-up of toxic free radicals).
Woman in typical paralysis extension from Parkinson's disease . Image by iAlbert_Londe (1889)
And interestingly, research has suggested that DJ-1 have an
important role in the protection against oxidative stress. For example, animals
where the gene has been removed are more vulnerable to toxic insults (usually
as result of oxidative stress), show abnormalities in the dopamine-producing
neurons and have motor problems. Dopaminergic neurons are known to have high
levels of oxidative stress because they tend to use large quantities of energy producing free
radicals as side products. On the other hand, overproduction of DJ-1 is found in
several different types of cancer, suggesting, again, an effect on cell
survival/death (a hallmark of all cancers is a resistance to cell death). Also
interesting is the fact that DJ-1 causes early-onset PD, so its loss seems to
mimic (early) whatever fails in ageing neurons.
In the research now published, Outeiro’s and Giorgini’s
teams used S. cerevisiae - the yeast
of bread - to investigate DJ-1 cellular role. Yeasts are good models to study
human genes because they are unicellular (1- cell, so very simple), but share
several genes with us, including a DJ-1 family. They also have a small genome
and a short lifespan, what means that their genetic manipulation is easy and
that the results show up quickly. More important, yeasts have a so-called “stationary phase” where they show
several characteristics of neural cells (like an incapacity to divide), and can
be used as a model for aging neurons.
To study DJ-1, Miller-Fleming and colleagues looked at
yeasts in “stationary phase”, comparing animals with and without the gene, and
found that
without DJ-1 yeasts are much more sensitive to oxidative stress, have a
shorter lifespan, and that these effects are mediated through TOCR1. DJ-1
depleted yeasts also show abnormalities in autophagy,
one of the cell’s “house-cleaning” mechanisms crucial for the elimination of
faulty and unnecessary cellular components.
Interestingly, the
three tenets of PD - oxidative stress, mitochondrial dysfunction, and protein
aggregation - can be all linked to autophagy, which is, after all, essential
for the elimination of malfunctioning and/or toxic products within the cell,
supporting the idea that these new results will be relevant for the human
disease
In conclusion Miller-Fleming, Outeiro, Giorgini’s new
research suggests that the DJ-1 family protects against oxidative stress by
controlling TOCR1, which we know regulates autophagy and cell survival. Once
DJ-1 is malfunctioning, problems in these processes could, no doubt, contribute
for the neural death of Parkinson’s. If repeated in humans (and problems in autophagy and
TORC1 have already been reported in PD) the results introduce DJ-1 as a
promising target for therapies for PD, cancer and even other neurodegenerative
diseases.
Every year hundreds of thousands of people around the world are
diagnosed with Parkinson’s. In the US alone 50,000 thousand new cases (6 new
cases every hour), with the total number of Americans with PD already in half a
million costing the government $25 billion a year. If we consider that the
chances of developing the disease increase with age - 1% of the population
above 65 years old, and 4% above 80 years, will develop it – it is easy to see how urgently it is to start understanding
PD.
PNAS 2014
- Yeast DJ-1 superfamily members are
required for diauxic-shift reprogramming and cell survival in stationary phase
Leonor Miller-Fleming, Pedro Antas, Teresa Faria Pais, Joshua L Smalley,
Flaviano Giorgini and Tiago Fleming Outeiro
www.pnas.org/cgi/doi/10.1073/pnas.1319221111
