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A Parkinson Disease Gene Discovered,
an Oncogene Remembered
| HOT
PAPERS
| DJ-1 spurs a rethink on neurodegenerative mechanisms | By Nicole Johnston
T
© 2004 Springer-Verlag
he discovery of several genes
linked to Parkinson disease
(PD) in recent years has
spawned extensive research efforts
GAPDH
to elucidate the underlying mechaRNA-binding
Apo
nism of this prevalent neurological
ptot
complex
ic si
disorder. This issue’s Hot Paper
gna
ls
focuses on the discovery of a third
gene, DJ-1, which is mutated in a
small subset of patients with PD.1
Transcription
Neurologist and geneticist Vincenzo
complex
Chaperone
Bonifati, along with molecular biolactivity
Protein
ogists Ben Oostra and Peter Heutink
DJ-1
misfolding
PIAS
and colleagues at Erasmus University Medical Center in Rotterdam,
showed that DJ-1 mutations are
SUMO-1
implicated in a form of autosomal
recessive, early-onset PD. Genetic
mapping of regions implicated in
Oxidative
parkinsonism among members of
sensor
DJ-1
ROS
two different families revealed a
pl 5.8
deletion in the DJ-1 gene among
members of one family, and a point
mutation in members of the other.
Interestingly, the gene had been
ls
discovered in a wholly different
gna
c si
i
t
context several years earlier by
o
pt
Apo
Hiroyashi Ariga and colleagues at
Mittoch
hondriaa
Hokkaido University in Sapporo.2
A sleeper of sorts, the paper was
rarely cited, but subsequent interCytoplasm
est in this earlier discovery exploded following the work from
Bonifati’s group, spawning a flurry
4 MULTITASKING?: DJ-1 might have chaperone activity, which helps to refold proteins in
the presence of oxidative stress and other cell stress contiditions. It may in fact sense
of citations and subsequent papers
in the past two years.
oxidative signals via oxidation at cysteine 106. DJ-1 might influence stress response
The work highlights the third
gene expression at transcriptional and post-transcriptional levels by interacting with
gene known to be linked to familial
PIAS and other nuclear cofactors and with cytosolic RNA-binding protein complexes.
Parkinsonism and has heightened
Such complexes may also be associated with GAPDH, which has functional links to apoptosis
interest in the function of the DJ-1
and Parkinson disease. (Adapted from V. Bonifati et al., J Mol Med, 82:163–74, 2004.)
protein. Perhaps more significantly,
the link renewed debate over
They did not, however, expect to find a gene already charactermechanistic theories of Parkinsonism and revived interest in the
role of oxidative stress to explain the disease mechanism, a theory ized. “Prior to our paper, there were maybe ten to fifteen papers
that had fallen by the wayside in the wake of α-synuclein and parkin, on DJ-1,” says Bonifati. Conditions were ripe for generating a lot
of attention.
the first two genes implicated in PD.3,4
“The [research] community was slow to jump on the first two
A BANDWAGON RUSH Heutink’s group made its discovery
based on genetic mapping of two consanguineous but genetically genes when they were cloned,” says Ted Dawson, a neurologist and
isolated families from the Netherlands and Italy, and he says it was molecular biologist at the Johns Hopkins University School of Medall based on a really good hunch. “We took a risky tactic to identify icine, Baltimore. “There were already big players in the α-synuclein
the gene. The region where the gene is located is pretty big, so we and parkin fields. I think people realized they had to jump on the
took a bit of an educated guess about what kind of mutation we’d bandwagon right away if they wanted to make an impact.” Now, he
find,” says study coauthor Peter Heutink, now at VU University Med- says, “Everybody and their mother is working on DJ-1 … because it’s
ical Center in Amsterdam. “We made a bit of a gamble and it worked.” small, soluble, has antibodies [against it], and has been crystallized.”
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The discovery also altered the research direction of individuals
who had been looking at DJ-1 for years before the PD link was made.
This study, says Oostra, “opened their eyes to a different function for
the gene and its protein.”
“We cloned the cDNA of DJ-1 and reported in 1997 that DJ-1 is a
novel oncogene in collaboration with ras,” says Ariga. Before the PD
discovery, Ariga says their DJ-1 research focused on the roles in cancer and reproduction. In some instances of male infertility, Ariga
explains, DJ-1 expression is reduced and the protein localizes incorrectly in sperm. A subsequent paper published by his team described
a role for DJ-1 in male infertility.5 Conversely, he says, DJ-1 is overexpressed in cancer cells, including breast, lung, and prostate cancers.
The impact of Bonifati’s discovery was felt before the paper’s
publication, however. Following a presentation of the Dutch group’s
work at a neuroscience meeting, Ariga recalls being contacted by
groups from all over the world wanting to work on DJ-1. “Many Emails from groups working on neurodegeneration … came to me
asking for DJ-1 cDNA and an anti-DJ-1 antibody,” he recalls. “We
were, of course, quite surprised at this discovery, but were glad that
the importance of DJ-1 could be recognized, in addition to our findings regarding reproduction.”
DJ-1 ALTERING DIRECTIONS The DJ-1 mutation affects only a
minority of individuals who have a sporadic form of Parkinson disease, but that hasn’t lessened its impact. “Mutations in α-synuclein,
the first Parkinson’s disease gene, have obviously been discovered
in only a very few patients as well,” says Oliver Bandmann, a neurologist and molecular biologist at the University of Sheffield, UK. But
the discovery of α-synuclein has greatly advanced the understanding of Parkinson disease; DJ-1 may be similarly revealing, he says.
“Naturally occurring variants in DJ-1 may be a susceptibility factor
for sporadic Parkinson’s disease.”
Indeed, the connection to PD triggered a rethinking of hypotheses proposed to explain disease pathogenesis and a redirecting of
some research efforts. A number of studies had localized DJ-1 to the
level of the mitochondria. Although it’s not clear whether the protein strictly localizes at the mitochondria, such results excite Serge
Przedborski, a cell biologist at Columbia University. “For many
years in this field, there has been a lingering idea that mitochondrial
dysfunction may play a part in the disease,” he says.
Ariga’s group in Japan was the first to show that DJ-1 exhibits
some anti-oxidant properties, a finding that implies a role for oxidative stress in Parkinson disease, says Przedborski. Ariga says their
recent work has identified roles for DJ-1 in transcriptional regulation, anti-oxidative stress, and mitochondrial function, and it also
demonstrates protease activity.
“The function of DJ-1 is still mostly unknown, although several
[proposed] functions have been put forward,” says Bonifati. Prelimi-
nary evidence suggests a role for DJ-1 as a molecular chaperone, a
mechanism implicated in other neurodegenerative diseases and
currently a matter of particular focus, he explains. Another prevailing theory is a role for DJ-1 as an antioxidant, but that theory, he
says, “is still quite controversial.”
Until now, research on the mutant parkin and α-synuclein proteins pointed towards protein degradation as the main culprit in the
pathogenesis of the disease, says Przedborski. “This was the first gene
product telling us that maybe it wasn’t just protein degradation. Ninety
percent of research efforts deal with protein degradation.” Neither the
mutant parkin nor α-synuclein discoveries suggested oxidative stress
or mitochondrial dysfunction, he explains. “Now that DJ-1 is coming
into play, maybe those mechanisms are involved in the cascade.”
“The protein degradation hypothesis had been buzzing around
because of the parkin gene,” says Heutink. The discovery of DJ-1 and
what was known about the nature of the protein, “brings back the
oxidative stress hypothesis that had been out of the spotlight for a
while,” he says. “It looks like it’s involved in oxidative stress. That’s
the picture that’s evolving.”
Indeed, says Ariga, “The brain of some sporadic form of Parkinson’s disease patients possessed abnormal forms of oxidized DJ-1.”
His group has recently found that oxidation of DJ-1 at three cysteine
residues adversely affects protein function, with one residue in particular, cysteine 106, being particularly crucial. “There are two types
of oxidation at C106 of DJ-1: sulfinic and sulfonic acids. It is, therefore, important to elucidate which oxidized form of DJ-1 is active or
inactive, leading to the onset of Parkinson’s disease.”
The discovery this past year of two additional genes linked to
PD—PINK 6 and PARK-8 7—has done little to clarify the culprits. To
date, the known genes affect only small patient subsets, yet Oostra
believes that identifying still more genes and characterizing the function of their products is revealing, each adding its respective piece to
the puzzle. “The challenge is to look for genes involved in Parkinson’s disease at all the ages,” says Oostra. “Hopefully at the end we’ll
understand the mechanism of developing Parkinson’s disease.” 6
YEARLY CITATIONS FOR NAGAKUBO ET AL. (1997)
5. K. Takahashi et al., “DJ-1 positively regulates the androgen receptor by impairing the
binding of PIASα· to the receptor,” J Biol Chem, 276:37556–63, 2001.
1997
1998
1999
2000
2001
2002
2003
2004
1. V. Bonifati et al., “Mutations in the DJ-1 gene associated with autosomal recessive
early-onset Parkinsonism,” Science, 299:256–9, 2003. (Cited in 180 papers)
2. D. Nagakubo et al., “DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in
cooperation with ras,” Biochem Biophys Res Comm, 231:509–13, 1997. (Cited in 74
papers)
3. M.H. Polymeropoulos et al., “Mutation in the α-synuclein gene identified in families
with Parkinson’s disease,” Science, 276:2045–7, 1997.
4. T. Kitada et al., “Mutations in the parkin gene cause autosomal recessive juvenile
parkinsonism,” Nature, 392:605–8, 1998.
7. C. Paisan-Ruiz et al., “Cloning of the gene containing mutations that cause PARK8linked Parkinson’s disease,” Neuron, 44:595–600, Nov. 18, 2004.
Data derived from the Science Watch/Hot Papers database and
the Web of Science (Thomson Scientific, Philadelphia) show
that Hot Papers are cited 50 to 100 times more often than the
average paper of the same type and age.
4 RESURRECTED: The paper first describing DJ-1 was cited
just a handful of times before researchers from The
Netherlands linked the gene to Parkinson disease.
March 14, 2005
References
6. E.M. Valente et al., “Hereditary early-onset Parkinson’s disease caused by mutations
in PINK1,” Science, 304:1158–60, 2004.
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2
2
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(Source: Histogram produced using HistCite software.)
Nicole Johnston ([email protected])
V. Bonifati et al., “Mutations in the DJ-1 gene associated with
autosomal recessive early-onset Parkinsonism,” Science,
299:256–9, 2003. (Cited in 180 papers)
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