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"Astrocytes!" Something new to me. Gives a whole new meaning to the concept
of "Inner space"...

Nic 57/15


On Thu, Apr 30, 2009 at 8:27 PM, mschild <[log in to unmask]> wrote:

> ScienceDaily (Apr. 30, 2009) — Scientists have identified a protein that
> appears not only to be central to the process that causes Parkinson's
> disease
> but could also play a role in muting the high from methamphetamine and
> other
> addictive drugs.
> The action of the protein, known as organic cation transporter 3 or oct3,
> fills a longstanding gap in scientists' understanding of the brain damage
> that
> causes symptoms like tremor, stiffness, slowness of movement and postural
> instability. While these are found mainly in patients with Parkinson's
> disease, there are more than three dozen other known causes of this array
> of
> symptoms, known as "parkinsonism."
> In a paper published online this week in the Proceedings of the National
> Academy of Sciences, scientists at the University of Rochester Medical
> Center
> and Columbia University have shown that oct3, a protein that shepherds
> molecules into and out of cells, plays a critical role, bringing toxic
> chemicals to the doorstep of the brain cells that die in patients with
> Parkinson's disease. The team found that oct3 is involved in the brain's
> response to addictive drugs like methamphetamine as well.
> Precisely what causes Parkinson's disease remains largely a mystery. Some
> cases have a known genetic basis, and most others are attributed to
> environmental causes or a combination of gene-environment interactions.
> Doctors know that symptoms of Parkinson's stem from the death of a very
> small,
> specialized group of brain cells known as dopamine neurons, which produce a
> chemical needed by another area of the brain to help us move freely. It's
> not
> until most of those brain cells have already died that patients begin to
> show
> symptoms.
> For decades, scientists have been trying to understand why those cells die.
> The latest paper supports a role for astrocytes, a type of cell that is the
> most common in the brain but which has been often overlooked by scientists
> focused more on cells known as neurons that send electrical signals.
> Astrocytes' role in Parkinson's is no surprise to brain experts who have
> also
> identified them as a player in Alzheimer's disease, amyotrophic lateral
> sclerosis, epilepsy, and other diseases.
> "Astrocytes are definitely much more than support cells in the brain," said
> Kim Tieu, Ph.D., a corresponding author of the paper and assistant
> professor
> in the Department of Environmental Medicine at the University of Rochester
> Medical Center. "Scientists are discovering their involvement in many
> diseases. The latest results point to their role in Parkinson's disease."
> Tieu initiated the study while a post-doctoral research associate in the
> laboratory of Serge Przedborski, M.D., Ph.D., the Page and William Black
> Professor of Neurology at Columbia University and a corresponding author.
> They
> chose to study how the brain handles a chemical known as MPTP, which
> ultimately damages the exact same brain cells that are injured in patients
> with Parkinson's disease. While MPTP does not cause Parkinson's disease,
> scientists regularly use it as a model for the disease because it causes an
> identical type of brain damage.
> In the brain, MPTP is converted primarily in astrocytes to a chemical
> called
> MPP+, which is deadly to dopamine neurons. More than 20 years ago, as a
> graduate student with Solomon Snyder, M.D., Jonathan Javitch, M.D., Ph.D.,
> now
> professor of psychiatry and pharmacology at Columbia and an author on the
> current paper, concluded that MPP+ is released from astrocytes before it
> kills
> dopaminergic neurons. But exactly how MPP+ is freed from astrocytes was
> unknown.
> In this week's PNAS paper, the scientists finger oct3 as the shepherd that
> escorts toxic MPP+ out of the astrocytes and into the space surrounding
> dopamine neurons. That's where another molecule known as the dopamine
> transporter picks it up and brings it into the neuron itself.
> When the team blocked or genetically removed oct3 in mice, the dopamine
> neurons in the brains did not die despite the presence of MPTP in the
> brain.
> Without oct3, MPP+ remained sequestered inside astrocytes and did not
> affect
> the dopamine neurons. And when oct3 was present in the usual amounts,
> dopamine
> neurons died as expected.
> "The neurons affected in Parkinson's disease don't live in isolation in the
> brain," said Przedborski. "You must understand the brain environment as a
> whole to understand disease. For many years, people had a neuron-centric
> view
> of neurodegenerative diseases. But more and more scientists are realizing
> that
> if you wish to understand the process of neurodegeneration, you must take
> into
> account the astrocytes, the microglia, as well as the neurons. Astrocytes
> maintain an intimate relationship with neurons, and to understand one, you
> have to understand the other."
> The team also analyzed brain tissue from people who died of Parkinson's
> disease and found that oct3 is active in astrocytes in the brain region
> affected by Parkinson's disease. They found the same thing in mice, where
> the
> absence of oct3 correlated exactly to areas of the brain where neurons were
> not damaged.
> The team also showed that oct3 plays a role in the brain's response to
> methamphetamine. Oct3 is critical for helping astrocytes soak up excess
> dopamine in the space around neurons. When dopamine isn't removed as
> quickly
> or thoroughly as usual, people can feel euphoric, but they can also
> experience
> brain damage. The finding that oct3 may play a role matches other
> scientists'
> observations that people in whom oct3 activity is reduced have a higher
> potential for addiction.
> The molecule might also offer a new target for treating depression. Many
> anti-
> depressants work by allowing the brain chemical serotonin to stay available
> in
> the brain longer than it otherwise would. Since one of oct3's functions is
> to
> remove serotonin from the brain, blocking it may offer a new avenue to
> treat
> depression.
> The chemicals that the team used to block oct3 in mice would be toxic in
> people, and there is no drug available for people now that blocks or boosts
> oct3, Tieu and Przedborski said. But such a drug might be useful for
> Parkinson's, drug addiction, and depression.
> "How you choose to manipulate the function of oct3 depends on the source of
> the toxic molecules," said Tieu, who is also a scientist in the
> University's
> Center for Neural Development and Disease. "You would try to lessen its
> effects in a condition where it makes a toxic molecule available to
> vulnerable
> cells, as illustrated in the current model of Parkinson's disease. But in
> the
> case of drug addiction, you might try to increase it, to lessen the impact
> of
> a drug like methamphetamine."
> Other authors at the University of Rochester include post-doctoral research
> associates Mei Cui, Ph.D., Radha Aras, Ph.D., and Mamata Hatwar, Ph.D.;
> graduate student Whitney Christian; medical and graduate student Phillip
> Rappold; former undergraduate student Joseph Panza; and Ned Ballatori,
> Ph.D.,
> professor of environmental medicine. At Columbia, Vernice Jackson-Lewis,
> Ph.D., associate research scientist, also contributed to the research. The
> work was funded by the National Institute of Environmental Health Sciences.
>
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