Transplanted cells could 'catch' Parkinson's

22:00 07 April 2008

NewScientist.com
news service
Peter Aldhous
Can cells transplanted into the brains of people with Parkinson's disease "catch" the disorder from the surrounding tissue?

That's the question raised by some perplexing new studies, providing another complication for researchers who are trying to develop advanced therapies based on neurons grown from stem cells.

The findings come from post-mortems of patients who received grafts of brain tissue from aborted fetuses during the 1990s. These grafts provided a fresh supply of cells that usually release the neurotransmitter dopamine, but which die off in patients with Parkinson's.

Two teams claim that some of the cells in the patients' grafts are now themselves showing signs of the disease.

The diseased cells contain structures called Lewy bodies, accumulations of a protein called α-synuclein that are a hallmark of Parkinson's. This is a surprise, as conventional wisdom suggests that the grafted cells, still only 11 to 16 years old, are too young to be affected in this way.

"We never see any α-synuclein until 40 years of age," says Jeffrey Kordower of Rush University Medical Center in Chicago.

Catch it
Kordower and his colleagues studied a woman who died 14 years after getting grafts of fetal brain tissue. The second team, led by Patrik Brundin of the Wallenberg Neuroscience Center in Lund, Sweden, found Lewy bodies in grafted neurons from two patients, who each received two grafts between 11 and 16 years before their deaths.

Fortunately, the vast majority of the grafted neurons in all three patients were free of Lewy bodies, which suggests that grafts may still offer some benefit even if they start to become affected by the disease.

But why the grafted neurons should be showing signs of Parkinson's is unclear. One provocative theory is that the disease crossed from the patient's own brain tissue, perhaps by an abnormal form of the α-synuclein protein in a process similar to that caused by the "prion" proteins implicated in mad cow disease.

Inflamed brain
Adding to the mystery, a third team, led by Ole Isacson of the McLean Hospital in Belmont, Massachusetts, has studied three further patients, finding no Lewy bodies.

Brundin points out that two of Isacson's patients had received their grafts 9 years before their deaths, suggesting that the problem takes longer than that to emerge. But Isacson suspects that the differences may reflect variations in the extent to which the patients' grafts triggered an inflammatory reaction.

Inflammation may be inherent to Parkinson's disease, and so difficult to avoid. But if the immune system is involved in the new-found problems, it provides additional impetus to develop "personalised" therapies, in which neurons are grown from a patient's own cells, and so should be less likely to provoke an immune reaction.

That prospect brightened this week, with the announcement from a team led by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, that dopamine-producing neurons grown from genetically "reprogrammed" mouse skin cells can ease Parkinson's-like symptoms in rats.

This means it should, in theory, be possible to take skin cells from a Parkinson's patient, reprogram them to an embryonic stem cell-like state, and then grow replacement neurons that would match to the patients' own brain tissue.

Clone or program
Jaenisch's study comes hard on the heels of experiments in which mice with a Parkinson's-like condition were successfully treated using genetically-matched neurons created by cloning, rather than genetic reprogramming.

But no one has yet succeeded in making human embryonic stem cells by cloning. And even if it is technically feasible, cloning requires large numbers of human eggs, which are in very short supply.

"Obtaining eggs is a pretty hopeless thing, in my opinion," says Jaenisch.

The genetic reprogramming technique does work with human cells. But before it could be used in people, researchers will need to achieve reprogramming without leaving behind copies of the genes involved, which can trigger cancer.

Journal references: Nature Medicine, DOI: 10.1038/nm1746, 10.1038/nm1747 and 10.1038/nm1752; Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0801677105

Mental Health - Discover the latest research in our continuously updated special report.

Stem Cells - Learn more about the promise and the controversy in our cutting edge special report .

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Weblinks
National Parkinson Foundation
http://www.parkinson.org
Cell therapy for Parkinson's disease
http://www.pubmedcentral.nih.gov/art...i?artid=534947

And why is medicine so fixated on treating symptom instead of addressing cause? Of course the transplanted cells start to die. They put them into an environment that was already killing similar cells! Whether it is my pet theory of stress and immune response or pesticides or mercury or whatever, until the underlying process is addressed, the best you can do is to buy time. Not that that is bad or anything....

dear rev -
I went to the psychiatrist last week - and she wondered why - I wasnt shaking, she asked me - what have I been doing, I told her -I was taking
a few supplements -and I mentioned ashwagandha, then she asked if I had told my neuro and I said -yes -
then she asked me -what he thought, and I relayed he thoughtit was good -
because he is from India -and Ayurveda is from his country -
I quoted hippocrates - let your food be your medicine -
and she could not understand how nutrtion was medicine?
____________

they are not taught to heal
they have been taught to give drug therapy?
drug therapy -does not cure...
also -
the education process - does not allow for "thinking outside of the text" -
and if you do happen to have a brilliant doctor -it is because -
he passed the tests and received the education ---

but this special doctor continues to learn - and does not like mediocre medicine, I have met many intelligent doctors -

but it is the ones with heart wisdom - that we admire most,
however the AMA does not care for them, and that is the problem...
and I have met only a few, and that is a great threat to bigpharma!

Well it's about time! From the first time I read an article about stem cells, I have said that these cells would die off too because they have not fixed whatever it is causing the cells to die off in the first place. I hope now that this is understood they can start looking for the real problem.

GregD

the same molecules that are killing our SN neurons are the result of a "transfect" of an intracellular process. Much in the same way that gene therapy relies on the transfer of specific bits of genetic information into a cell to "turn on" some "good process", we are getting gene transfer from compromised cells to "clean" cells.
A long time ago, it was suggested that dopamine itself was the culprit itself. Much work suggested that this was not true. But then we now have something staring us right in the face so to speak. It all began with the discovery that some molecules which are structurally related to dopamine are actually potent killers of DA neurons. One of them particularly intrigues me. This molecule isx 6-hydroxy-dopamine. It is just too simple! The addition of another hydroxy group at the 6-position of the aryl ring in dopamine, turns it into a "killer" molecule.
THis has been proven by the fact that 6-hydroxy-dopamine is used in laboratories to "give" rats a parkinsonian condition, known as the "contralateral rotation test" This test is done by injecting this molecule (or the use of MPTP, or a few other known specific SN cell killers) into one of the two SN structures (these SN structures occur in both "halves" of the brain). After some time has past (a few short weeks), the animal is PD compromised on that side of the body. The animal is always "hemiparkinsonized" never "globally parkinsonized" because only one piece of the dopamine producing SN has had a majority of it's cells killed off because only one side is injected with the toxin.
Now comes the part thati am not sure of. Does anyone know if hey have kept these rats alive long enough to see if "Globalization" occurs? That is, does the experimantal "parkinsonization" of one side of the brain "spread" to affect the other side, and most important, if it does, how and why does it do this?
Ever since i learned of this "supertoxic parkinsonizer", 6-hydroxy-dopamine, i said to myself "it's so very similar in structure to dopamine, just one simple little hydroxy group attached at the 6-position of the dopamine aryl ring, why is it so effective in the killing of DA neurons? Well, i won't get into the proposed mechanism, but the fact remains, 6-hydroxydopamine selectively kills off DA neurons.
So, we have something right in our hands , right now, that we know causes PDism. MY question has been out there for years now. IT is " do we have an enzyme which by mutation of that enzyme, results in an isozyme that can 6-hydroxylate dopamine" This would be the "cause of PD" as i see it. Maybe the enzyme is very inefficient at performing this chemical transformation, so something has been missed in the extensive studies of the question of whether dopamine itself is at the root of PD. Maybe it does it's dirty work only in the presence of specific low concentration co-factors,and has thus been missed, because only attomolar concentrations of 6-hydroxydopamine are produced and are at this concentration indetectable, but nevertheless remains the true "root of PD".
Thus, any healthy DA neuron isn't safe in the presence of this almost indetectable process. You can put new cells, but you haven't addressed the question of protecting them from this insidious "cloaked" killer.
If we could trace this molecule (or something similar to it) as teh "Silent kiler of DA neurons", then we could have a shot at halting or with the implant of healthy cells , reversing the process of the continuing neuron loss that is PD.
REmember, we all lose a small percentage of DA neurons every year of life, but us PWP lose too many too quickly. This fact fits right in with a "slow silent killer" whose rate of DA neuron destruction is different for everyone.
IMHO, this is not too difficult of a biochemical detective story. Give us a lab, hire a few of the world's best biologist and chemist post-docs, a toxicologist, maybe a brain surgeon, and a top of the line GC-LC MS operator, and other things like capillary electrophoresis as tools and a few pathologists and they could have an answer to this question. This would go a long way to get at the "heart" of PD. cs

I know little of chemistry and expect to be dead wrong, but this caught my eye. First of all, there is the involvement of my pet gram-negative bacteria's toxins. Second, there is the necessity for iron's involvement. Does it lead anywhere?


1: Biochemistry. 2008 Mar 4;47(9):2814-25. Epub 2008 Feb 7.

An inner membrane dioxygenase that generates the 2-hydroxymyristate moiety of
Salmonella lipid A.

Gibbons HS, Reynolds CM, Guan Z, Raetz CR.

Department of Biochemistry, Duke University Medical Center, Durham, North
Carolina 27710, USA.

The lipid A residues of certain Gram-negative bacteria, including most strains of
Salmonella and Pseudomonas, are esterified with one or two secondary
S-2-hydroxyacyl chains. The S-2 hydroxylation process is O 2-dependent in vivo,
but the relevant enzymatic pathways have not been fully characterized because in
vitro assays have not been developed. We previously reported that expression of
the Salmonella lpxO gene confers upon Escherichia coli K-12 the ability to
synthesize 2-hydroxymyristate modified lipid A ( J. Biol. Chem. (2000) 275,
32940-32949). We now demonstrate that inactivation of lpxO, which encodes a
putative Fe (2+)/O 2/alpha-ketoglutarate-dependent dioxygenase, abolishes
S-2-hydroxymyristate formation in S. typhimurium. Membranes of E. coli strains
expressing lpxO are able to hydroxylate Kdo 2-[4'- (32)P]-lipid A in vitro in the
presence of Fe (2+), O 2, alpha-ketoglutarate, ascorbate, and Triton X-100. The
Fe (2+) chelator 2,2'-bipyridyl inhibits the reaction. The product generated in
vitro is a monohydroxylated Kdo 2-lipid A derivative. The [4'- (32)P]-lipid A
released by mild acid hydrolysis from the in vitro product migrates with
authentic S-2-hydroxlyated lipid A isolated from (32)P-labeled S. typhimurium
cells. Electrospray ionization mass spectrometry and gas chromatography/mass
spectrometry of the in vitro product are consistent with the 2-hydroxylation of
the 3'-secondary myristoyl chain of Kdo 2-lipid A. LpxO contains two predicted
trans-membrane helices (one at each end of the protein), and its active site
likely faces the cytoplasm. LpxO is an unusual example of an integral membrane
protein that is a member of the Fe (2+)/O 2/alpha-ketoglutarate-dependent
dioxygenase family.


PMID: 18254598 [PubMed - indexed for MEDLINE]