Tracing
Parkinson's lethal mechanism
In the vast majority of Parkinson’s disease (PD) patients,
the disorder arises not because of a genetic
defect, but because some external insult
triggers the death of dopamine-producing
neurons. Now, researchers have reported progress
in understanding the mechanism underlying that
death, which they say suggests a new treatment
pathway.
In both mice and human patients, the researchers have found
evidence that neurons die because of a crippling
of a particular protective enzyme that
eliminates potentially damaging “reactive oxygen
species” normally generated in the cell’s power
plants, called mitochondria.
David Park, of the Ottawa Health Research Institute, and
colleagues published their findings in the July
5, 2007 issue of the journal Neuron, published
by Cell Press.
The researchers studied the mechanism of PD using a mouse
model of the disease, in which a
mitochondria-affecting toxin called MPTP is used
to produce Parkinson’s-like brain pathology. In
earlier studies, they had found that MPTP
activates protein-snipping enzymes called
calpains in mitochondria. They also found
evidence that calpains, in turn, activate a
cellular switch called Cdk5. The question,
however, was how this abnormal activation
ultimately kills neurons.
In their new studies, the researchers analyzed neurons to
determine that Cdk5 regulates yet another
enzyme called Prx2. This enzyme is known as
a peroxidase and acts to render harmless the
chemically active reactive oxygen species
that are produced inside mitochondria in the
process of generating energy for the cell.
Specifically, the researchers found that treating neurons
with MPTP activates Cdk5 to switch off Prx2.
What’s more, they found that activating Prx2 in
MPTP-treated mice prevented the loss of
dopamine-producing neurons. And they
experimentally demonstrated that the action of
Cdk5 on Prx2 “plays a pivotal role” in the
neuronal damage from MPTP.
Importantly, the researchers discovered evidence that the
loss of Prx2 activity also plays a role in human
PD. They found reduced Prx2 activity in brain
tissue from PD patients.
“These findings provide a mechanistic link of how a
mitochondrial damaging agent, through calpain-mediated
Cdk5 activation and downregulation of an
important antioxidant enzyme, can increase
oxidative load, leading ultimately to death,”
concluded the scientists.
“Taken together, our findings suggest that strategies to
modulate Prx2 activity serve as beneficial
targets for treatment of PD,” they concluded.
“This is of particular importance since Cdk5 is
thought to have normal beneficial roles in
neurons and modulating a relevant downstream
target rather than Cdk5 directly may be a better
therapeutic strategy with regard to this
pathway.”
###
The researchers include Dianbo Qu, Juliet Rashidian, Matthew
P. Mount, Hossein Aleyasin, Mohammad Parsanejad,
Arman Lira, Emdadul Haque, Yi Zhang, Steve
Callaghan, Mireille Daigle, Maxime W.C.
Rousseaux, Ruth S. Slack, Paul R. Albert, John
M. Woulfe, and David S. Park of University of
Ottawa, Ottawa, Ontario, Canada; Inez Vincent of
University of British Columbia, Vancouver,
British Columbia, Canada.
This work was partially supported by the Parkinson's Disease
Foundation and the Parkinson's Society of Canada
(D.Q.) and the Heart and Stroke Foundation (J.R.,
H.A.) and by funds from the Canadian Institutes
of Health Research, the Parkinson’s Society
Canada, the Parkinson’s Disease Foundation, the
Parkinson’s Research Consortium, the US army,
and the Heart and Stroke Foundation of Ontario (D.S.P.).
Qu et al.: “Role of Cdk5-Mediated Phosphorylation of Prx2 in
MPTP Toxicity and Parkinson’s Disease.”
Publishing in Neuron 55, 37–52, July 5, 2007.
DOI 10.1016/j.neuron.2007.05.033.
www.neuron.org.
