A channel to neurodegeneration

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© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
NEWS AND VIEWS
occurs in response to chronically low blood
flow, was blocked in the P2X4 receptor–deficient mice.
As these findings provide insight into
the molecular mechanisms underlying
vascular tone and remodeling, the authors
speculate that this report may help develop
new therapies for blood pressure disorders. Unfortunately, selective agonists and
antagonists for the P2X4 receptors are not
yet available. ATPγS is a potent but not selective P2X4 agonist, whereas the nonspecific
P2 receptor antagonists suramin, pyridoxal
phosphate-6-azophenyl-2’, 4’-disulphonic
acid and Reactive blue 2 do not inhibit P2X4
receptor–mediated responses; indeed they
potentiate the ATP response by inhibiting
ectonucleotidases4. The wide variation in
vascular control by purines and pyrimidines
must also be recognized; further investigation is needed to establish which vessels in
which species use P2X 4 receptors as the
principal endothelial P2 receptor subtype
mediating release of nitric oxide.
The importance of purinergic signaling
in cardiovascular diseases12 is highlighted
by the recent use of P2Y12 receptor antagonists, like clopidogrel, for the treatment of
thrombosis and stroke—by the use of P1
receptor agonists, such as adenosine, for
treatment of supraventricular tachycardia
(rapid heart rate originating in the lower
heart chambers).
Although considerable effort has been
expended to produce selective agonists
and antagonists for P1 and P2 receptor
subtypes 13 , drugs that target the
different subtypes, including the P2X 4
receptor, and that are not degraded in vivo,
are still awaited.
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A channel to neurodegeneration
Ariel Y Deutch & Danny G Winder
In people with Parkinson disease, neurons in certain brain regions are more likely to die than others. A potassium
channel may be the key to understanding this differential neuronal death.
Neurodegenerative disorders are bigots. None
attack all brain cells, and many discretely target neurons in only a few areas. Why there is
a loss of midbrain dopamine neurons that
are next to ones spared in Parkinson disease
is intensely studied. In a surprising twist on
the usual suspects, a study in the December
issue of Nature Neuroscience may explain the
differential vulnerability of dopamine cells in
Parkinson disease1.
In Parkinson disease, dysfunction of the
mitochondrial electron transport chain,
increases in reactive oxygen species, and
decreases in ATP production contribute to
dopamine cell death in the substantia nigra2, a
region in the midbrain. The dopamine neurons
of the substantia nigra, and the striatal dopamine innervation derived from these neurons,
Ariel Y. Deutch is in the Departments of Psychiatry
and Pharmacology, and the National Parkinson
Foundation Center of Excellence at Vanderbilt
University; Danny G. Winder is in the Department
of Molecular Physiology and Biophysics and
the National Parkinson Foundation Center of
Excellence at Vanderbilt University, Vanderbilt
University Medical Center, Nashville, Tennessee
37212, USA.
E-mail: [email protected]
undergo a selective (or regionally specific)
pattern of degeneration in Parkinson disease.
Symptoms arise when dopamine axons in the
striatum are lost. In contrast, the dopamine
neurons in an adjacent midbrain region, the
ventral tegmental area, are much less affected.
What governs the differential loss of midbrain dopamine neurons in Parkinson disease
remains a source of speculation. Potential
explanations include differing degrees of
expression of the dopamine transporter
(through which xenobiotics access dopamine
neurons), the presence or absence of the calcium binding protein calbindin, and variations
in molecules that counter oxidative stress4,5.
But none of these explanations has proven
completely satisfactory.
Liss et al. now provide evidence that ATPsensitive potassium (KATP) channels may help
determine the selective loss of substantia nigra,
but not ventral tegmental area, dopamine
cells in Parkinson disease1. KATP channels are
metabolic sensors that couple cellular energy
metabolism to membrane potential by regulating potassium flux. In the midbrain dopamine
neurons, the KATP channels are composed of
a pore-forming inward-rectifying potassium
channel subunit known as Kir6.2 and a regulatory sulfonylurea receptor subunit known as
NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006
Sur1. Sulfonylureas are drugs used in the
treatment of type 2 diabetes that close KATP
channels and densely bind neurons of the
substantia nigra.
Liss et al. reported that the mRNA encoding KATP channels comprising Kir6.2 and
Sur1 are abundantly expressed in substantia
nigra dopamine neurons. They found that
metabolic challenges with parkinsonisminducing toxins, such as MPTP, cause rapid
hyperpolarization and electrical ‘silencing’
of dopamine cells in the substantia nigra,
but not in the ventral tegmental area. In
contrast, nigral dopamine neurons from
Kir6.2 knockout mice were not hyperpolarized with these toxins.
MPTP treatment of mice causes extensive loss of substantia nigra dopamine neurons and the dopamine innervation of the
striatum6; in contrast, Liss et al. found that
Kir6.2 knockout mice are relatively resistant
to MPTP. When weaver mice— which suffer a developmentally specific loss of substantia nigra neurons7—were crossed with
Kir6.2 null mice, the absence of KATP channels attenuated the loss of substantia nigra
dopamine neurons in these mice. These
studies suggest that the KATP channel may
help determine whether a dopamine neuron
17
© 2006 Nature Publishing Group http://www.nature.com/naturemedicine
NEWS AND VIEWS
higher levels of uncoupling protein UCP-2 than
KATP Silencing of
UCP-2
do vulnerable substantia
dopamine neurons
nigra neurons, and mild
mitochondrial uncoupling
decreases KATP channel
VTA
Substantia
nigra
function. This suggests that
UCP-2 may be upstream
of KATP in determining
vulnerability of dopamine
neurons (Fig. 1). Another
recent study reported that
Figure 1 In Parkinson disease, only certain dopamine neurons in
adjacent regions of the midbrain are lost; Liss et al. report a potential
UCP-2 knockout mice
explanation. High expression of KATP channels in the dopamine
show increased MPTPneurons of the substantia nigra may trigger preferential cell death. On
induced neuronal death8.
the other hand, lower expression of this channel and higher expression
A major question now is
of the uncoupling protein UCP-2 in dopamine neurons of the ventral
how KATP channel–meditegmental area (VTA) may block neuron loss.
ated silencing of dopamine
lives or dies. The work may also open the door neurons triggers cell death. This finding runs
for new therapeutic strategies aimed at slowing counter to prevailing notions that neurodegeneration is associated with hyper- rather
the progression of Parkinson disease.
If KATP channels govern differential vul- than hypoexcitability. One could envision
nerability of dopamine neurons in Parkinson that KATP-induced silencing of dopamine
disease, it would provide a mechanism for neuron activity ultimately works through a
the coupling of metabolic disturbances in series of interconnected brain regions, which
dopamine neurons with functional effects on may also underlie the therapeutic effects of
membrane potential and cell firing. The KATP deep brain stimulation in Parkinson disease.
channel, however, is downstream of the meta- Alternatively, decreased membrane excitability
bolic perturbations. Accordingly, the patholog- and firing rate of dopamine neurons may disical process involving dopamine neurons must rupt autaptic trophic support (self-produced
occur before KATP channel–induced silencing growth factors). Regardless of the downstream
of dopamine neurons. Therefore, it is likely mechanism, the work of Liss et al. suggests that
that KATP channels are not the sole mediators neuronal silence may not always be golden.
Individuals with Parkinson disease also
of degeneration in dopamine neurons.
Interestingly, Liss et al. noted that ventral have an impaired insulin response to glutegmental area dopamine neurons express cose9. Sulfonylurea drugs, which are used to
treat type II diabetes, block KATP channels. The
findings of Liss et al. suggest that such drugs
may be useful in the treatment of Parkinson
disease and may reduce the risk, or slow the
progression, of the illness. We are unaware
of any epidemiological studies that report
an association between Sur1 or Kir6.2 and
Parkinson disease; such a study is warranted.
Clinical trials in parkinsonism with tolbutamide—a sulfonylurea drug—conducted before
the modern era of therapies for Parkinson
disease were inconclusive10. The data hinted,
however, that this drug may be effective in less
severely affected individuals with Parkinson
disease. If dopamine neurons have not yet
degenerated, perhaps KATP channel antagonists could slow disease progression.
The work of Liss et al. provides sorely
needed new targets for slowing the progressive loss of dopamine neurons in Parkinson
disease. Perhaps the new targets will allow us
to reach a point where all dopamine neurons
are left behind.
1. Liss, B. et al. Nature Neurosci. 8, 1742–1751
(2005).
2. Moore, D J., West, A.B., Dawson, V.L., & Dawson, T.M.
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54, 388–396 (1991)
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Neurobiol. Dis. 18, 19–31 (2005)
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(1984).
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U. J. Endocrinol. 59, 523–534 (1973).
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181–184 (1965).
Envoys of metastasis
Bone marrow cells lodged throughout the body seed the development of
metastases in mice, report Rosandra Kaplan and colleagues (Nature 438,
820–827). What’s more, blocking a signal from the marrow cells can prevent
the migration of metastatic cells to these locations.
The researchers first observed that bone marrow cells clustered at premetastatic locations before the arrival of tumor cells. These progenitor bone
marrow cells were identified using markers typical of such cells. The cells
also expressed vascular endothelial growth factor receptor-1 (VEGFR1), which
seemed to be necessary for migration of metastatic cells. Shown is one such
cluster of marrow cells (VEGFR1 in red, GFP-labeled marrow cell in green and
DNA in blue).
It is unclear what causes the bone marrow cells to cluster in the first place.
But in mice with tumors, expression of a protein that sticks to bone marrow
cells, fibronectin, was somehow increased at organs that conventionally host
metastatic tumors.
To show the involvement of VEGFR1, the researchers grew tumor cells in
the presence of VEGFR1-expressing cells; as a result, the tumor cells adhered more strongly and divided more rapidly. VEGFR1 cells
isolated from pre-metastatic clusters secreted growth factors, which may attract circulating tumor cells.
Finally, antibodies that blocked VEGFR1 completely prevented metastases in animals with established tumors. To date VEGF
inhibitors have been used in clinical trials with the aim of thwarting angiogenesis and tumor blood supply. The findings suggest that
they might be of use to block metastasis.
Allison Alcivar
18
VOLUME 12 | NUMBER 1 | JANUARY 2006 NATURE MEDICINE
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